Compounds for inhibition of alpha 4 beta 7 integrin

ABSTRACT

or a pharmaceutically acceptable salt thereof as described herein. The present disclosure also provides pharmaceutical compositions comprising a compound of Formula (I), processes for preparing compounds of Formula (I), therapeutic methods for treating inflammatory disease.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/886,798, filed on Aug. 14, 2019, the entire content of which ishereby incorporated by reference in its entirety.

FIELD

The present disclosure relates generally to novel compounds that haveα4β7 integrin inhibitory action, prodrugs of compounds having α4β7integrin inhibitory action, and methods of use and manufacture thereof.

BACKGROUND

Integrins are heterodimeric cell surface proteins involved in numerouscellular processes including cell-cell and cell-extracellular matrixinteractions. Upon binding of an extracellular ligand, integrins mediatesignal transduction to the cell interior resulting in lymphocyte cellcapture, adhesion, and infiltration into the tissue.

Integrins are heterodimeric proteins consisting of an alpha and a betasubunit. There are 18 known alpha subunits and 8 known beta subunits.The α4β7 integrin is expressed on the surface of lymphocytes andrecognizes the extracellular ligand mucosal addressing cell adhesionmolecule-1 (MAdCAM-1). α4β7 integrin governs lymphocyte trafficking toand retention in gut tissues through its interaction with MAdCAM-1,which is expressed on venules in the intestinal mucosa and highendothelial venules (HEV) in the gut-associated lymphoid tissues (GALT).Inhibiting the interactions of integrins with their respective ligandshas been proposed as an effective method of treating a variety ofautoimmune and inflammatory diseases, and blocking the α4β7-MAdCAM-1interaction has shown therapeutic benefit in inflammatory bowel disease(Crohn's disease and ulcerative colitis).

There is a need to for improved α4β7 integrin antagonist molecules forthe treatment of autoimmune and inflammatory diseases, includinginflammatory bowel disease.

SUMMARY

The present disclosure provides compounds that are inhibitors for α4β7integrin. The disclosure also provides compositions, includingpharmaceutical compositions, kits that include the compounds, andmethods of using (or administering) and making the compounds. Thecompounds provided herein are useful in treating diseases, disorders, orconditions that are mediated by α4β7 integrin. The disclosure alsoprovides compounds for use in therapy. The disclosure further providescompounds for use in a method of treating a disease, disorder, orcondition that is mediated by α4β7 integrin. Moreover, the disclosureprovides uses of the compounds in the manufacture of a medicament forthe treatment of a disease, disorder or condition that is mediated byα4β7 integrin.

In one aspect, provided is a compound having the structure of Formula(I), or a pharmaceutically acceptable salt thereof:

or a pharmaceutically acceptable salt thereof, wherein:

is a single or double bond; wherein A is an aromatic ring;

each Z¹, Z², Z³, and Z⁴ is independently selected from N, N(CR^(c)),C(O), and CR^(c); wherein each R^(c) is independently selected from H,halo, cyano, hydroxyl, —NR^(a1)R^(a2), C₁₋₄alkyl, C₁₋₄alkoxyl,C₁₋₄haloalkyl, and C₁₋₄haloalkoxyl;

R¹ is 5-10 membered heteroaryl or 6-10 membered heterocyclyl;

-   -   wherein each 5-10 membered heteroaryl and 6-10 membered        heterocyclyl of R¹ contains one to four N and optionally one to        three C(O) as a ring member(s); and    -   wherein each 5-10 membered heteroaryl and 6-10 membered        heterocyclyl of R¹ is optionally substituted with one to four        R^(a); and wherein each R^(a) is independently selected from        halo, cyano, hydroxyl, —NR^(a1)R^(a2), C₁₋₄alkyl, C₁₋₄alkoxyl,        C₁₋₄haloalkyl, C₁₋₄haloalkoxyl, —C₁₋₄alkylene-O—C₁₋₄alkyl, and        C₃₋₁₀cycloalkyl;

each R², R³, R⁵, and R⁶ is independently selected from H, halo, cyano,hydroxyl, —NR^(a1)R^(a2), C₁₋₄alkyl, C₁₋₄alkoxyl, C₁₋₄haloalkyl, andC₁₋₄haloalkoxyl;

R⁴ is selected from 3-10 membered heterocyclyl, 5-10 memberedheteroaryl, and —NR^(b1)R^(b2).

-   -   wherein the 3-10 membered heterocyclyl and 5-10 membered        heteroaryl of R⁴ is optionally substituted with one to six        R^(b); and wherein each R^(b) is independently selected from        halo, cyano, hydroxyl, —NR^(a1)R^(a2), C₁₋₆alkyl, C₁₋₆alkoxyl,        C₁₋₈haloalkyl, and C₁₋₈haloalkoxyl; and    -   wherein each R^(b1) and R^(b2) is independently selected from H,        C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, —C₁₋₆alkylene-phenyl,        and —C₁₋₆haloalkylene-phenyl;

R⁷ is selected from H, C₁₋₁₀alkyl, C₁₋₁₀haloalkyl, C₃₋₁₀cycloalkyl, 3-14membered heterocyclyl, C₆₋₁₀aryl, 5-10 membered heteroaryl,—C₁₋₄alkylene-NR^(a1)R^(a2), —C₁₋₄alkylene-C(O)NR^(a1)R^(a2),—C₁₋₄alkylene-C₃₋₁₀cycloalkyl, —C₁₋₄alkylene-3-14 membered heterocyclyl,—C₁₋₄alkylene-C₆₋₁₀aryl, —C₁₋₄alkylene-5-10 membered heteroaryl, and-L¹-R⁹;

-   -   wherein L¹ is selected from —C₁₋₄alkylene-O—,        —C₁₋₄alkylene-C(O)—, —C₁₋₄alkylene-O—C(O)—,        —C₁₋₄alkylene-O—C(O)—C₄alkylene-, —C₁₋₄alkylene-C(O)—O—,        —C₁₋₄alkylene-C(O)—O—C₁₋₄alkylene-, —C₁₋₄alkylene-O—C(O)—O—,        —C₁₋₄alkylene-O—C(O)—O—C₁₋₄alkylene-,        —C₁₋₄alkylene-NR^(a1)C(O)—O—, and —C₁₋₄alkylene-O—C(O)—NR^(a1)—;

R⁹ is selected from C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-14membered heterocyclyl, C₆₋₁₀aryl, and 5-10 membered heteroaryl;

-   -   wherein each C₃₋₁₀cycloalkyl, 3-14 membered heterocyclyl,        C₆₋₁₀aryl, and 5-10 membered heteroaryl of R⁷ and R⁹ is        optionally substituted with one to four groups independently        selected from halo, hydroxyl, C₁₋₄alkyl, C₁₋₄alkoxyl,        C₁₋₄haloalkyl, C₁₋₄haloalkoxyl, —NR^(a1)R^(a2), and        —C₁₋₄alkylene-NR^(a1)R^(a2);

R⁸ is selected from H, C₁₋₆alkyl, and C₁₋₆haloalkyl; and

each R^(a1) and R^(a2) is independently selected from H, C₁₋₆alkyl,C₁₋₆haloalkyl, and C₃₋₁₀cycloalkyl.

DETAILED DESCRIPTION Definitions and General Parameters

The following description sets forth exemplary methods, parameters andthe like. It should be recognized, however, that such description is notintended as a limitation on the scope of the present disclosure but isinstead provided as a description of exemplary embodiments.

As used in the present specification, the following words, phrases andsymbols are generally intended to have the meanings as set forth below,except to the extent that the context in which they are used indicatesotherwise.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom. A dash at the front or end of achemical group is a matter of convenience; chemical groups may bedepicted with or without one or more dashes without losing theirordinary meaning. A wavy line drawn through a line in a structureindicates a point of attachment of a group. Unless chemically orstructurally required, no directionality is indicated or implied by theorder in which a chemical group is written or named.

A squiggly line on a chemical group as shown below, for example,

indicates a point of attachment, i.e., it shows the broken bond by whichthe group is connected to another described group.

The prefix “C_(u-v)” indicates that the following group has from u to vcarbon atoms. For example, “C₁₋₈ alkyl” indicates that the alkyl grouphas from 1 to 8 carbon atoms.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. In certain embodiments, the term “about” includes the indicatedamount ±10%. In other embodiments, the term “about” includes theindicated amount ±5%. In certain other embodiments, the term “about”includes the indicated amount ±1%. Also, to the term “about X” includesdescription of “X”. Also, the singular forms “a” and “the” includeplural references unless the context clearly dictates otherwise. Thus,e.g., reference to “the compound” includes a plurality of such compoundsand reference to “the assay” includes reference to one or more assaysand equivalents thereof known to those skilled in the art.

“Alkyl” refers to an unbranched or branched saturated hydrocarbon chain.As used herein, alkyl has 1 to 20 carbon atoms (i.e., C₁₋₂₀ alkyl), 1 to8 carbon atoms (i.e., C₁₋₈ alkyl), 1 to 6 carbon atoms (i.e., C₁₋₆alkyl), or 1 to 4 carbon atoms (i.e., C₁₋₄ alkyl). Examples of alkylgroups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl,2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having aspecific number of carbons is named by chemical name or identified bymolecular formula, all positional isomers having that number of carbonsmay be encompassed; thus, for example, “butyl” includes n-butyl (i.e.—(CH₂)₃CH₃), sec-butyl (i.e. —CH(CH₃)CH₂CH₃), isobutyl (i.e.—CH₂CH(CH₃)₂) and tert-butyl (i.e. —C(CH₃)₃); and “propyl” includesn-propyl (i.e. —(CH₂)₂CH₃) and isopropyl (i.e. —CH(CH₃)₂).

“Alkylene” (including those which are part of other groups) refers tobranched and unbranched divalent “alkyl” groups. As used herein,alkylene has 1 to 20 carbon atoms (i.e., C₁₋₂₀alkylene), 1 to 8 carbonatoms (i.e., C₁₋₃ alkylene), 1 to 6 carbon atoms (i.e., C₁₋₆ alkylene),or 1 to 4 carbon atoms (i.e., C₁₋₄ alkylene). Examples include:methylene, ethylene, propylene, 1-methylethylene, butylene,1-methylpropylene, 1,1-dimethylethylene or 1,2-dimethylethylene. Unlessstated otherwise, the definitions propylene and butylene include all thepossible isomeric forms of the groups in question with the same numberof carbons. Thus, for example, propylene also includes 1-methylethyleneand butylene includes 1-methylpropylene, 1,1-dimethylethylene, and1,2-dimethylethylene.

“Alkenyl” refers to an aliphatic group containing at least onecarbon-carbon double bond and having from 2 to 20 carbon atoms (i.e.,C₂₋₂₀ alkenyl), 2 to 8 carbon atoms (i.e., C₂₋₈ alkenyl), 2 to 6 carbonatoms (i.e., C₂₋₆ alkenyl), or 2 to 4 carbon atoms (i.e., C₂₋₄ alkenyl).Examples of alkenyl groups include ethenyl, propenyl, butadienyl(including 1,2-butadienyl and 1,3-butadienyl).

“Alkynyl” refers to an aliphatic group containing at least onecarbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e.,C₂₋₂₀ alkynyl), 2 to 8 carbon atoms (i.e., C₂₋₈ alkynyl), 2 to 6 carbonatoms (i.e., C₂₋₆ alkynyl), or 2 to 4 carbon atoms (i.e., C₂₋₄ alkynyl).The term “alkynyl” also includes those groups having one triple bond andone double bond.

“Alkoxy” and “alkoxyl” are used interchangeably and refer to the group“alkyl-O—”. Examples of alkoxyl and alkoxy groups include methoxy,ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy,n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. “Haloalkoxyl” refers to analkoxyl group as defined above, wherein one or more hydrogen atoms arereplaced by a halogen.

“Acyl” refers to a group —C(═O)R, wherein R is hydrogen, alkyl,cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each ofwhich may be optionally substituted, as defined herein. Examples of acylinclude formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethyl-carbonyl,and benzoyl.

“Aryl” refers to an aromatic carbocyclic group having a single ring(e.g. monocyclic) or multiple rings (e.g. bicyclic or tricyclic)including fused systems. As used herein, aryl has 6 to 20 ring carbonatoms (i.e., C₆₋₂₀ aryl), 6 to 12 carbon ring atoms (i.e., C₆₋₁₂ aryl),or 6 to 10 carbon ring atoms (i.e., C₆₋₁₀ aryl). Examples of aryl groupsinclude phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, doesnot encompass or overlap in any way with heteroaryl defined below. Ifone or more aryl groups are fused with a heteroaryl ring, the resultingring system is heteroaryl.

“Azido” refers to the group —N₃.

“Cyano” or “carbonitrile” refers to the group —CN.

“Cycloalkyl” refers to a saturated or partially saturated cyclic alkylgroup having a single ring or multiple rings including fused, bridged,and spiro ring systems. The term “cycloalkyl” includes cycloalkenylgroups (i.e. the cyclic group having at least one double bond). As usedherein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C₃₋₂₀cycloalkyl), 3 to 12 ring carbon atoms (i.e., C₃₋₁₂ cycloalkyl), 3 to 10ring carbon atoms (i.e., C₃₋₁₀ cycloalkyl), 3 to 8 ring carbon atoms(i.e., C₃₋₈ cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C₃₋₆cycloalkyl). Examples of cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups also includepartially unsaturated ring systems containing one or more double bonds,including fused ring systems with one aromatic ring and one non-aromaticring, but not fully aromatic ring systems.

“Bridged” refers to a ring fusion wherein non-adjacent atoms on a ringare joined by a divalent substituent, such as an alkylenyl orheteroalkylenyl group or a single heteroatom. Quinuclidinyl andadmantanyl are examples of bridged ring systems.

The term “fused” refers to a ring which is bound to an adjacent ring.

“Halogen” or “halo” includes fluoro, chloro, bromo, and iodo.

“Haloalkyl” refers to an unbranched or branched alkyl group as definedabove, wherein one or more hydrogen atoms are replaced by a halogen. Forexample, where a residue is substituted with more than one halogen, itmay be referred to by using a prefix corresponding to the number ofhalogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkylsubstituted with two (“di”) or three (“tri”) halo groups, which may be,but are not necessarily, the same halogen. Examples of haloalkyl includedifluoromethyl (—CHF₂) and trifluoromethyl (—CF₃).

“Haloalkylene” refers to an unbranched or branched alkylene group asdefined above, wherein one or more hydrogen atoms are replaced by ahalogen.

The term “heterocyclyl” or “heterocycle” as used herein refers to asingle saturated or partially unsaturated non-aromatic ring or anon-aromatic multiple ring system that has at least one heteroatom inthe ring (i.e., at least one annular heteroatom selected from O, N, S,S(O), S(O)₂, and N-oxide groups). Unless otherwise specified, aheterocyclyl group has from 3 to about 20 annular atoms, for examplefrom 3 to 12 annular atoms, for example from 3 to 10 annular atoms, forexample from 5 to 10 annular atoms or for example from 5 to 6 annularatoms. Thus, the term includes single saturated or partially unsaturatedrings (e.g., 3, 4, 5, 6 or 7-membered rings) having from about 1 to 6annular carbon atoms and from about 1 to 3 annular heteroatomsindependently selected from the group consisting of O, N, S, S(O),S(O)₂, and N-oxide in the ring. The rings of the multiple condensed ring(e.g. bicyclic heterocyclyl) system can be connected to each other viafused, spiro and bridged bonds when allowed by valency requirements.Heterocycles include, but are not limited to, groups derived fromazetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide),oxetane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine,pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine,tetrahydropyridine, tetrahydro-2H-thiopyran 1,1-dioxide, quinuclidine,N-bromopyrrolidine, N-chloropiperidine, and the like. Heterocyclesinclude spirocycles, such as, for example, aza or oxo-spiroheptanes.Heterocyclyl groups also include partially unsaturated ring systemscontaining one or more double bonds, including fused ring systems withone aromatic ring and one non-aromatic ring, but not fully aromatic ringsystems. Examples include dihydroquinolines, e.g. 3,4-dihydroquinoline,dihydroisoquinolines, e.g. 1,2-dihydroisoquinoline, dihydroimidazole,tetrahydroimidazole, etc., indoline, isoindoline, isoindolones (e.g.isoindolin-1-one), isatin, dihydrophthalazine, quinolinone,spiro[cyclopropane-1,1′-isoindolin]-3′-one, and the like. Additionalexamples of heterocycles include 3,8-diazabicyclo[3.2.1]octanyl,2,5-diazabicyclo [2.2.1]heptanyl, 3,6-diazabicyclo[3.1.1]heptanyl,3-oxa-7,9-diazabicyclo[3.3.1]nonanyl, andhexahydropyrazino[2,1-c][1,4]oxazinyl, for example.

“Hydroxyl” and “hydroxy” are used interchangeably and refer to —OH.“Oxo” refers to the group (═O) or (O). Where tautomeric forms of thecompound exist, hydroxyl and oxo groups are interchangeable.

“Heteroaryl” refers to an aromatic group, including groups having anaromatic tautomer or resonance structure, having a single ring, multiplerings, or multiple fused rings, with at least one heteroatom in thering, i.e., one or more ring heteroatoms independently selected fromnitrogen, oxygen, and sulfur, wherein the nitrogen or sulfur may beoxidized. Thus, the term includes rings having one or more annular O, N,S, S(O), S(O)₂, and N-oxide groups. The term includes rings having oneor more annular C(O) groups. As used herein, heteroaryl include 5 to 20ring atoms (i.e., 5- to 20-membered heteroaryl), 5 to 12 ring atoms(i.e., 5- to 12-membered heteroaryl), or 5 to 10 ring atoms (i.e., 5- to10-membered heteroaryl), and 1 to 5 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, and oxidized forms of theheteroatoms. Examples of heteroaryl groups include pyridin-2(1H)-one,pyridazin-3(2H)-one, pyrimidin-4(3H)-one, quinolin-2(1H)-one,pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, andpyrazolyl. Heteroaryl does not encompass or overlap with aryl as definedabove.

“Sulfonyl” refers to the group —S(O)₂R, where R is alkyl, haloalkyl,heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl aremethylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

Whenever the graphical representation of a group terminates in a singlybonded nitrogen atom, that group represents an —NH group unlessotherwise indicated. Similarly, unless otherwise expressed, hydrogenatom(s) are implied and deemed present where necessary in view of theknowledge of one of skill in the art to complete valency or providestability.

Certain commonly used alternative chemical names may be used. Forexample, a divalent group such as a divalent “alkyl” group, a divalent“aryl” group, etc., may also be referred to as an “alkylene” group or an“alkylenyl” group, an “arylene” group or an “arylenyl” group,respectively. Also, unless indicated explicitly otherwise, wherecombinations of groups are referred to herein as one moiety, e.g.arylalkyl, the last mentioned group contains the atom by which themoiety is attached to the rest of the molecule.

The terms “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where said event or circumstance occursand instances in which it does not. Also, the term “optionallysubstituted” refers to any one or more hydrogen atoms on the designatedatom or group may or may not be replaced by a moiety other thanhydrogen.

The term “substituted” means that any one or more hydrogen atoms on thedesignated atom or group is replaced with one or more substituents otherthan hydrogen, provided that the designated atom's normal valence is notexceeded. The one or more substituents include, but are not limited to,alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl,azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo,haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino,imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl,thiocyanate, thiol, thione, or combinations thereof. Polymers or similarindefinite structures arrived at by defining substituents with furthersubstituents appended ad infinitum (e.g., a substituted aryl having asubstituted alkyl which is itself substituted with a substituted arylgroup, which is further substituted by a substituted heteroalkyl group,etc.) are not intended for inclusion herein. Unless otherwise noted, themaximum number of serial substitutions in compounds described herein isthree. For example, serial substitutions of substituted aryl groups withtwo other substituted aryl groups are limited to ((substitutedaryl)substituted aryl) substituted aryl. Similarly, the abovedefinitions are not intended to include impermissible substitutionpatterns (e.g., methyl substituted with 5 fluorines or heteroaryl groupshaving two adjacent oxygen ring atoms). Such impermissible substitutionpatterns are well known to the skilled artisan. When used to modify achemical group, the term “substituted” may describe other chemicalgroups defined herein. For example, the term “substituted aryl”includes, but is not limited to, “alkylaryl.” Unless specifiedotherwise, where a group is described as optionally substituted, anysubstituents of the group are themselves unsubstituted.

In some embodiments, the term “substituted alkyl” refers to an alkylgroup having one or more substituents including hydroxyl, halo, alkoxy,cycloalkyl, heterocyclyl, aryl, and heteroaryl. In additionalembodiments, “substituted cycloalkyl” refers to a cycloalkyl grouphaving one or more substituents including alkyl, haloalkyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, alkoxy, halo, oxo, and hydroxyl;“substituted heterocyclyl” refers to a heterocyclyl group having one ormore substituents including alkyl, haloalkyl, heterocyclyl, cycloalkyl,aryl, heteroaryl, alkoxy, halo, oxo, and hydroxyl; “substituted aryl”refers to an aryl group having one or more substituents including halo,alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, alkoxy, andcyano; “substituted heteroaryl” refers to an heteroaryl group having oneor more substituents including halo, alkyl, haloalkyl, heterocyclyl,heteroaryl, alkoxy, and cyano and “substituted sulfonyl” refers to agroup —S(O)₂R, in which R is substituted with one or more substituentsincluding alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Inother embodiments, the one or more substituents may be furthersubstituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl,heterocyclyl, aryl, or heteroaryl, each of which is substituted. Inother embodiments, the substituents may be further substituted withhalo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl,aryl, or heteroaryl, each of which is unsubstituted.

Some of the compounds exist as tautomeric isomers. Tautomeric isomersare in equilibrium with one another. For example, amide containingcompounds may exist in equilibrium with imidic acid tautomers.Regardless of which tautomer is shown, and regardless of the nature ofthe equilibrium among tautomers, the compounds are understood by one ofordinary skill in the art to comprise both amide and imidic acidtautomers. Thus, the amide containing compounds are understood toinclude their imidic acid tautomers. Likewise, the imidic acidcontaining compounds are understood to include their amide tautomers.

Any formula or structure given herein, is also intended to representunlabeled forms as well as isotopically labeled forms of the compounds.Isotopically labeled compounds have structures depicted by the formulasgiven herein except that one or more atoms are replaced by an atomhaving a selected atomic mass or mass number. Examples of isotopes thatcan be incorporated into compounds of the disclosure include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as, but not limited to ²H (deuterium, D), ³H (tritium), ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶Cl and ¹²⁵I. Various isotopicallylabeled compounds of the present disclosure, for example those intowhich radioactive isotopes such as ³H, ¹³C and ¹⁴C are incorporated.Such isotopically labelled compounds may be useful in metabolic studies,reaction kinetic studies, detection or imaging techniques, such aspositron emission tomography (PET) or single-photon emission computedtomography (SPECT) including drug or substrate tissue distributionassays or in radioactive treatment of patients.

The disclosure also includes compounds of the present disclosure, inwhich from 1 to n hydrogens attached to a carbon atom is/are replaced bydeuterium, in which n is the number of hydrogens in the molecule. Suchcompounds exhibit increased resistance to metabolism and are thus usefulfor increasing the half-life of any compound of the present disclosure,when administered to a mammal, particularly a human. See, for example,Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,”Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds aresynthesized by means well known in the art, for example by employingstarting materials in which one or more hydrogens have been replaced bydeuterium.

Deuterium labelled or substituted therapeutic compounds of thedisclosure may have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to distribution, metabolism and excretion (ADME).Substitution with heavier isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life, reduced dosage requirements and/oran improvement in therapeutic index. An ¹⁸F labeled compound may beuseful for PET or SPECT studies. Isotopically labeled compounds of thisdisclosure and prodrugs thereof can generally be prepared by carryingout the procedures disclosed in the schemes or in the examples andpreparations described below by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent. Itis understood that deuterium in this context is regarded as asubstituent in the compound of the present disclosure.

The concentration of such a heavier isotope, specifically deuterium, maybe defined by an isotopic enrichment factor. In the compounds of thisdisclosure any atom not specifically designated as a particular isotopeis meant to represent any stable isotope of that atom. Unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural abundanceisotopic composition. Accordingly, in the compounds of this disclosureany atom specifically designated as a deuterium (D) is meant torepresent deuterium.

In many cases, the compounds of this disclosure are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

The term “pharmaceutically acceptable salt” of a given compound refersto salts that retain the biological effectiveness and properties of thegiven compound, and which are not biologically or otherwise undesirable.Pharmaceutically acceptable base addition salts can be prepared frominorganic and organic bases. Salts derived from inorganic bases include,by way of example only, sodium, potassium, lithium, ammonium, calciumand magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary and tertiary amines, such asalkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines,di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenylamines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines,di(substituted alkenyl) amines, tri(substituted alkenyl) amines, mono,di or tri cycloalkyl amines, mono, di or tri arylamines or mixed amines,etc. Specific examples of suitable amines include, by way of exampleonly, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl)amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol,piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

Pharmaceutically acceptable acid addition salts may be prepared frominorganic and organic acids. Salts derived from inorganic acids includehydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. Salts derived from organic acids includeacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,malic acid, malonic acid, succinic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid,salicylic acid, and the like.

As used herein, “pharmaceutically acceptable carrier” or“pharmaceutically acceptable excipient” includes any and all solvents,dispersion media, coatings, antibacterial and antifungal agents,isotonic and absorption delaying agents and the like. The use of suchmedia and agents for pharmaceutically active substances is well known inthe art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

“Treatment” or “treating” is an approach for obtaining beneficial ordesired results including clinical results. Beneficial or desiredclinical results may include one or more of the following: a) inhibitingthe disease or condition (e.g., decreasing one or more symptomsresulting from the disease or condition, and/or diminishing the extentof the disease or condition); b) slowing or arresting the development ofone or more clinical symptoms associated with the disease or condition(e.g., stabilizing the disease or condition, preventing or delaying theworsening or progression of the disease or condition, and/or preventingor delaying the spread (e.g., metastasis) of the disease or condition);and/or c) relieving the disease, that is, causing the regression ofclinical symptoms (e.g., ameliorating the disease state, providingpartial or total remission of the disease or condition, enhancing effectof another medication, delaying the progression of the disease,increasing the quality of life, and/or prolonging survival.

“Prevention” or “preventing” means any treatment of a disease orcondition that causes the clinical symptoms of the disease or conditionnot to develop. Compounds may, in some embodiments, be administered to asubject (including a human) who is at risk or has a family history ofthe disease or condition.

“Subject” refers to an animal, such as a mammal (including a human),that has been or will be the object of treatment, observation orexperiment. The methods described herein may be useful in human therapyand/or veterinary applications. In some embodiments, the subject is amammal. In one embodiment, the subject is a human.

The term “therapeutically effective amount” or “effective amount” of acompound described herein or pharmaceutically acceptable salts, isomer,or a mixture thereof means an amount sufficient to effect treatment whenadministered to a subject, to provide a therapeutic benefit such asamelioration of symptoms or slowing of disease progression. For example,a therapeutically effective amount may be an amount sufficient todecrease a symptom of a disease or condition responsive to inhibition ofα4β7 integrin activity. The therapeutically effective amount may varydepending on the subject, and disease or condition being treated, theweight and age of the subject, the severity of the disease or condition,and the manner of administering, which can readily be determined by oneor ordinary skill in the art.

The term “inhibition” indicates a decrease in the baseline activity of abiological activity or process. “Inhibition of activity of α4β7integrin” or variants thereof refers to a decrease in activity of α4β7integrin as a direct or indirect response to the presence of a compoundof the present application relative to the activity of α4β7 integrin inthe absence of the compound of the present application. “Inhibition ofα4β7” refers to a decrease in α4β7 integrin activity as a direct orindirect response to the presence of a compound described hereinrelative to the activity of α4β7 integrin in the absence of the compounddescribed herein. In some embodiments, the inhibition of α4β7 integrinactivity may be compared in the same subject prior to treatment, orother subjects not receiving the treatment.

Compounds

Provided herein are compounds that function as inhibitors of α4β7integrin. In one aspect, provided is a compound having structure ofFormula (I), or a pharmaceutically acceptable salt thereof:

or a pharmaceutically acceptable salt thereof, wherein:

is a single or double bond; wherein A is an aromatic ring;

each Z¹, Z², Z³, and Z⁴ is independently selected from N, N(CR^(c)),C(O), and CR^(c); wherein each R^(c) is independently selected from H,halo, cyano, hydroxyl, —NR^(a1)R^(a2), C₁₋₄alkyl, C₁₋₄alkoxyl,C₁₋₄haloalkyl, and C₁₋₄haloalkoxyl;

R¹ is 5-10 membered heteroaryl or 6-10 membered heterocyclyl;

-   -   wherein each 5-10 membered heteroaryl and 6-10 membered        heterocyclyl of R¹ contains one to four N and optionally one to        three C(O) as a ring member(s); and    -   wherein each 5-10 membered heteroaryl and 6-10 membered        heterocyclyl of R¹ is optionally substituted with one to four        R^(a); and wherein each R^(a) is independently selected from        halo, cyano, hydroxyl, —NR^(a1)R^(a2), C₁₋₄alkyl, C₁₋₄alkoxyl,        C₁₋₄haloalkyl, C₁₋₄haloalkoxyl, —C₁₋₄alkylene-O—C₁₋₄alkyl, and        C₃₋₁₀cycloalkyl;

each R², R³, R⁵, and R⁶ is independently selected from H, halo, cyano,hydroxyl, —NR^(a1)R^(a2), C₁₋₄alkyl, C₁₋₄alkoxyl, C₁₋₄haloalkyl, andC₁₋₄haloalkoxyl;

R⁴ is selected from 3-10 membered heterocyclyl, 5-10 memberedheteroaryl, and —NR^(b1)R^(b2);

-   -   wherein the 3-10 membered heterocyclyl and 5-10 membered        heteroaryl of R⁴ is optionally substituted with one to six        R^(b); and wherein each R^(b) is independently selected from        halo, cyano, hydroxyl, —NR^(a1)R^(a2), C₁₋₆alkyl, C₁₋₆alkoxyl,        C₁₋₈haloalkyl, and C₁₋₈haloalkoxyl; and    -   wherein each R^(b1) and R^(b2) is independently selected from H,        C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, —C₁₋₆alkylene-phenyl,        and —C₁₋₆haloalkylene-phenyl;

R⁷ is selected from H, C₁₋₁₀alkyl, C₁₋₁₀haloalkyl, C₃₋₁₀cycloalkyl, 3-14membered heterocyclyl, C₆₋₁₀aryl, 5-10 membered heteroaryl,—C₁₋₄alkylene-NR^(a1)R^(a2), —C₁₋₄alkylene-C(O)NR^(a1)R^(a2),—C₁₋₄alkylene-C₃₋₁₀cycloalkyl, —C₁₋₄alkylene-3-14 membered heterocyclyl,—C₁₋₄alkylene-C₆₋₁₀aryl, —C₁₋₄alkylene-5-10 membered heteroaryl, and-L¹-R⁹;

-   -   wherein L¹ is selected from —C₁₋₄alkylene-O—,        —C₁₋₄alkylene-C(O)—, —C₁₋₄alkylene-O—C(O)—,        —C₁₋₄alkylene-O—C(O)—C₄alkylene-, —C₁₋₄alkylene-C(O)—O—,        —C₁₋₄alkylene-C(O)—O—C₁₋₄alkylene-, —C₁₋₄alkylene-O—C(O)—O—,        —C₁₋₄alkylene-O—C(O)—O—C₁₋₄alkylene-,        —C₁₋₄alkylene-NR^(a1)C(O)—O—, and —C₁₋₄alkylene-O—C(O)—NR^(a1)—;

R⁹ is selected from C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-14membered heterocyclyl, C₆₋₁₀aryl, and 5-10 membered heteroaryl;

-   -   wherein each C₃₋₁₀cycloalkyl, 3-14 membered heterocyclyl,        C₆₋₁₀aryl, and 5-10 membered heteroaryl of R⁷ and R⁹ is        optionally substituted with one to four groups independently        selected from halo, hydroxyl, C₁₋₄alkyl, C₁₋₄alkoxyl,        C₁₋₄haloalkyl, C₁₋₄haloalkoxyl, —NR^(a1)R^(a2), and        —C₁₋₄alkylene-NR^(a1)R^(a2);

R⁸ is selected from H, C₁₋₆alkyl, and C₁₋₆haloalkyl; and

each R^(a1) and R^(a2) is independently selected from H, C₁₋₆alkyl,C₁₋₆haloalkyl, and C₃₋₁₀cycloalkyl.

In another aspect, provided are compounds of Formula (II), orpharmaceutically acceptable salts thereof:

wherein R¹, R², R⁴, R⁶, and R⁷ are as defined above in formula (I), orelsewhere in this disclosure.

In another aspect, provided are compounds of Formula (IIa), orpharmaceutically acceptable salts thereof:

wherein R², R⁴, R⁶, R⁷, and R^(a) are as defined above in formula (I),(II), or elsewhere in this disclosure. Y¹ is N or CH. R^(d) is selectedfrom H, C₁₋₄alkyl, and C₁₋₄haloalkyl; and r is selected from 0, 1, 2,and 3.

In another aspect, provided are compounds of Formula (IIb), orpharmaceutically acceptable salts thereof:

wherein R^(a), R², R⁶, R⁷, and R^(b) are as defined above in formula(I), (II), or elsewhere in this disclosure. X¹ is selected from CR^(x1),and N. X² is selected from CR^(x1)R^(x2), NR^(x2), and O. R^(x1) isselected from H, and R^(b); and R^(x2) is selected from H, C₁₋₄alkyl,and C₁₋₄haloalkyl. R^(d) is selected from H, C₁₋₄alkyl, andC₁₋₄haloalkyl. r is selected from 0, 1, 2, and 3; and m is selected from0, 1, 2, 3, and 4.

In another aspect, provided are compounds of Formula (IIc), orpharmaceutically acceptable salts thereof:

wherein R², R⁶, and R⁷ are as defined above in formula (I), (II), orelsewhere in this disclosure. R^(b) is C₁₋₄alkyl, or C₁₋₆haloalkyl.R^(d) is selected from H, C₁₋₄alkyl, and C₁₋₄haloalkyl.

In another aspect, provided are compounds of Formula (Id), orpharmaceutically acceptable salts thereof:

wherein R⁷ is as defined above in formula (I), (II), or elsewhere inthis disclosure. Each R² and R⁶ is independently selected from halo,C₁₋₄alkyl and C₁₋₄haloalkyl. R^(b) is C₁₋₄alkyl, or C₁₋₆haloalkyl. R^(d)is H, C₁₋₄alkyl, or C₁₋₄haloalkyl.

In another aspect, provided are compounds of Formula (III), orpharmaceutically acceptable salts thereof:

wherein R¹, R², R⁴, R⁶, R⁷, and R^(c) are as defined above in formula(I), or elsewhere in this disclosure.

In another aspect, provided are compounds of Formula (IIIa), orpharmaceutically acceptable salts thereof:

wherein R¹, R², R⁶, R⁷, R^(b), and R^(c) are as defined above in formula(I), or elsewhere in this disclosure. X¹ is selected from CR^(x1), andN. X² is selected from CR^(x1)R^(x2), NR^(x2), and O. R^(x1) is selectedfrom H, and R^(b). R^(x2) is selected from H, C₁₋₄alkyl, andC₁₋₄haloalkyl. m is selected from 0, 1, and 2.

In another aspect, provided are compounds of Formula (IIIb), orpharmaceutically acceptable salts thereof:

wherein R¹, R², R⁶, R⁷, and R^(c) are as defined above in formula (I),or elsewhere in this disclosure. R⁷. R^(b) is C₁₋₄alkyl, orC₁₋₆haloalkyl.

In another aspect, provided are compounds of Formula (IV), orpharmaceutically acceptable salts thereof:

wherein R¹, R², R⁴, R⁶, R⁷, and R^(c) are as defined above in formula(I), or elsewhere in this disclosure.

In some embodiments of formula (I), (II), (III), (IIIa), or (IIIb), R¹is selected from pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl,quinolinyl, isoquinolinyl, isoxazolyl, triazolyl, pyrazolyl,benzothiazolyl, pyridinonyl, quinolinonyl, isoquinolinonyl,quinazolinedionyl, pyrazinonyl, pyrimidinonyl, pyrimidinedionyl,pyridazinonyl, and quinazolinonyl. Each R¹ is independently optionallysubstituted with one to four R^(a).

In some embodiments of formula (I), (II), (III), (IIIa), or (IIIb), R¹is selected from:

wherein each R¹ is independently optionally substituted with one tothree R^(a). In some embodiments, R¹ is selected from:

wherein each R¹ is independently optionally substituted with one tothree R^(a). In some embodiments, each R^(a) is independently selectedfrom halo, CN, —OH, NR^(a1)R^(a2), C₁₋₄alkyl, C₁₋₄alkoxyl,C₁₋₄haloalkyl, and C₁₋₄haloalkoxyl. In some embodiments, each R^(a) isindependently selected from F, C, OH, CN, —NH₂, —N(CH₃)₂, —CH₃, —CH₂F,—CHF₂, —CF₃, —OCH₃, and —OCF₃.

In some embodiments of formula (I), (II), (III), (IIIa), or (IIIb), R¹is

and R^(d) is C₁₋₄alky. In some embodiments, R^(d) is methyl or ethyl. Insome embodiments, R^(d) is methyl. In some embodiments, R¹ is

In some embodiments of formula (I), (II), (III), (IIIa), or (IIIb), R¹is

optionally substituted with one to three R^(a). In some embodiments, R¹is selected from

In some embodiments, R¹ is

In some embodiments of formula (I), (II), (III), (IIIa), or (IIIb), R¹is 10 membered heterocyclyl containing two N and two C(O) as ringmembers, and R¹ is optionally substituted with one to three R^(a). Insome embodiments, each R^(a) is independently selected from F, Cl, OH,CN, —NH₂, —N(CH₃)₂, —CH₃, —CH₂F, —CHF₂, —CF₃, —OCH₃, and —OCF₃. In someembodiments, R¹ is selected from

each of which is optionally substituted with one to three R^(a). In someembodiments, R^(d) is —CH₃. In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments of formula (I), (II), (III), (IIIa), or (IIIb), R¹is

In some embodiments of formula (I), (II), (III), (IIIa), or (IIIb), R¹is

In some embodiments, R^(d) is —CH₃. In some embodiments, R¹ is

In some embodiments of formula (I), Z¹ is N. Z², Z³, and Z⁴ are CR^(c).In some embodiments, Z¹ is N; and Z², Z³, and Z⁴ are CH. In someembodiments, Z³ is N; and Z¹, Z², and Z⁴ are CR^(c). In someembodiments, Z¹ and Z² are N. In some embodiments, Z¹ and Z³ are N. Insome embodiments, Z¹ is CR^(c); and R^(c) is selected from C₁₋₄alkyl,C₁₋₄alkoxyl, C₁₋₄haloalkyl, and C₁₋₄haloalkoxyl. In some embodiments, Z¹is CR^(c), and R^(c) is selected from —CH₃, —OCH₃, and —CF₃. In someembodiments, Z¹ is C—OCH₃.

In some embodiments of formula (I), each R³ and R⁵ is independentlyselected from H, and halo. In some embodiments, each R³ and R⁵ is H.

In some embodiments of formula (I), (II), (IIa), (IIb), (IIc), (IId),(III), (IIIa), or (IIIb), each R² and R⁶ is independently selected fromH, halo, C₁₋₄alkyl, C₁₋₄alkoxyl, C₁₋₄haloalkyl, and C₁₋₄haloalkoxyl. Insome embodiments, each R² and R⁶ is independently selected from F, and—CH₃. In some embodiments, R² is F, and R⁶ is —CH₃.

In some embodiments of formula (I), (II), (IIa), or (III), R⁴ is 3-8membered heterocyclyl optionally substituted with one to three R^(b). Insome embodiments, the 3-8 membered heterocyclyl of R⁴ contains one totwo heteroatoms or groups independently selected from S, N, O, andS(O)₂. In some embodiments, each R^(b) is independently selected fromhalo, hydroxyl, cyano, —NR^(a1)R^(a2), C₁₋₄alkyl, C₁₋₄alkoxyl, andC₁₋₄haloalkyl. In some embodiments, each R^(b) is independently selectedfrom F, Cl, CN, —OH, —CH₃, —CH(CH₃)₂, —CF₃, and —CH₂CF₃.

In some embodiments of formula (I), (II), (IIa), or (II), R⁴ is6-membered heterocyclyl optionally substituted with one to three R^(b).In some embodiments, R⁴ is selected from

and each of which is optionally substituted with one to three R^(b). Insome embodiments, each R^(b) is independently selected from halo,C₁₋₄alkyl, and C₁₋₄haloalkyl. In some embodiments, R⁴ is

optionally substituted with R^(b); and R^(b) is selected from —CH₃,—CHF₂, —CF₃, and —CH₂CF₃. In some embodiments, R^(b) is selected from—CH₃, —CHF₂, and —CF₃. In some embodiments, R^(b) is selected from—CH₂CHF₂, and —CH₂CF₃. In some embodiments, R⁴ is selected from

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments of formula (I), (II), (IIa), or (III), R⁴ is

In some embodiments

In some embodiments of formula (I), (II), (IIa), or (III), R⁴ is—NR^(b1)R^(b2). In some embodiments, each R^(b1) and R^(b2) isindependently selected from H, C₁₋₆alkyl, C₁₋₆haloalkyl, andC₃₋₆cycloalkyl. In some embodiments, R^(b1) is H and R^(b2) isC₁₋₆haloalkyl. In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments of formula (I), (II), (IIa), or (III), R⁴ is 5-10membered heteroaryl optionally substituted with one to three R^(b); andeach R^(b) is independently selected from halo, C₁₋₄alkyl, andC₁₋₄haloalkyl. In some embodiments, R⁴ is 5 membered heteroaryloptionally substituted with one to three R^(b). In some embodiments, R⁴is pyrrolyl optionally substituted with one to three R^(b). In someembodiments, R⁴ is imidazolyl optionally substituted with one to threeR^(b). In some embodiments, each R^(b) is independently selected from—CH₃, —CHF₂, —CF₃, and —CH₂CF₃. In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R^(b) is selected from —CH₃, —CHF₂, —CF₃, and—CH₂CF₃.

In some embodiments of formula (IIb), or (IIa), X¹ is N, and X² is O. Insome embodiments, X¹ is N. In some embodiments, X¹ and X² are N. In someembodiments, X² is O. In some embodiments, X² is CR^(x1)R^(x2), R^(x1)is selected from H and C₁₋₄alkyl, and R^(x2) is H. In some embodiments,X² is —CH₂—.

In some embodiments of formula (III), (IIIa), or (IIIb), R^(c) isselected from halo, C₁₋₄ alkyl, C₁₋₄alkoxyl, C₁₋₄haloalkyl, andC₁₋₄haloalkoxyl. In some embodiments, R^(c) is selected from F, CI, CH₃,—OCH₃, —OCF₃, and —CF₃. In some embodiments, R^(c) is —OCH₃.

In some embodiments of formula (I), (II), (IIa), (IIb), (IIc), (Id),(III), (IIIa), or (IIIb), R⁷ is selected from H, C₁₋₆alkyl, andC₃₋₆cycloalkyl. In some embodiments, R⁷ is selected from H, C₁₋₆alkyl,and C₃₋₆cycloalkyl. R⁷ is selected from H, methyl, ethyl, propyl, butyl,cyclopropyl, —CH₂—O—C(O)C(CH)₃, and phenyl. In some embodiments, R⁷ isselected from H, methyl, ethyl, propyl, and cyclopropyl. In someembodiments, R⁷ is selected from H, methyl, ethyl, propyl, butyl,—CH₂C(O)N(CH₃)₂, —(CH₂)₂N(CH₂CH₃)₂, —CH₂—O—C(O)CH₃, —(CH₂)₂—O—C(O)CH₃,—CH₂—O—C(O)C(CH)₃, —(CH₂)₂—O—C(O)C(CH)₃, —CH₂—O—C(O)—O—CH₃,—CH(CH₃)—O—C(O)—O—CH₃, —CH₂—O—C(O)—O—CH₂CH₃, —CH₂—O—C(O)—O—CH(CH₃)₂,—CH₂—O—C(O)—O—C(CH₃)₃, and —(CH₂)₂C(O)CH₃. In some embodiments, R⁷ is H.In some embodiments, R⁷ is methyl. In some embodiments, R⁷ is ethyl. Insome embodiments, R⁷ is cyclopropyl. In some embodiments, R⁷ is phenyl.

In some embodiments of formula (I), R⁸ is H.

In some embodiments, the compound of the present disclosure is selectedfrom examples 1-53.

In some embodiments, the compound of the present disclosure is selectedfrom examples 54-93.

Provided are also compounds described herein or pharmaceuticallyacceptable salts, isomer, or a mixture thereof, in which from 1 to nhydrogen atoms attached to a carbon atom may be replaced by a deuteriumatom or D, in which n is the number of hydrogen atoms in the molecule.As known in the art, the deuterium atom is a non-radioactive isotope ofthe hydrogen atom. Such compounds may increase resistance to metabolism,and thus may be useful for increasing the half-life of the compoundsdescribed herein or pharmaceutically acceptable salts, isomer, or amixture thereof when administered to a mammal. See, e.g., Foster,“Deuterium Isotope Effects in Studies of Drug Metabolism”, TrendsPharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized bymeans well known in the art, for example by employing starting materialsin which one or more hydrogen atoms have been replaced by deuterium.

In some embodiments, the compound of the present disclosure contains oneto six deuterium (²H, or D). In some embodiments, one of R², R³, R⁴, R⁵,and R⁶contains one to six D. In some embodiments, R⁶contains one to sixD. In some embodiments, R⁶ is CD₃.

Provided are also pharmaceutically acceptable salts, hydrates, solvates,tautomeric forms, polymorphs, and prodrugs of the compounds describedherein. “Pharmaceutically acceptable” or “physiologically acceptable”refer to compounds, salts, compositions, dosage forms and othermaterials which are useful in preparing a pharmaceutical compositionthat is suitable for veterinary or human pharmaceutical use.“Pharmaceutically acceptable salts” or “physiologically acceptablesalts” include, for example, salts with inorganic acids and salts withan organic acid. In addition, if the compounds described herein areobtained as an acid addition salt, the free base can be obtained bybasifying a solution of the acid salt. Conversely, if the product is afree base, an addition salt, particularly a pharmaceutically acceptableaddition salt, may be produced by dissolving the free base in a suitableorganic solvent and treating the solution with an acid, in accordancewith conventional procedures for preparing acid addition salts from basecompounds. Those skilled in the art will recognize various syntheticmethodologies that may be used to prepare nontoxic pharmaceuticallyacceptable addition salts.

A “solvate” is formed by the interaction of a solvent and a compound.Solvates of salts of the compounds described herein are also provided.Hydrates of the compounds described herein are also provided.

A “prodrug” is a biologically inactive derivative of a drug that uponadministration to the human body is converted to the biologically activeparent drug according to some chemical or enzymatic pathway.

In certain embodiments, provided are optical isomers, racemates, orother mixtures thereof of the compounds described herein orpharmaceutically acceptable salts or a mixture thereof. In thosesituations, the single enantiomer or diastereomer, i.e., opticallyactive form, can be obtained by asymmetric synthesis or by resolution ofthe racemate. Resolution of racemates can be accomplished, for example,by conventional methods such as crystallization in the presence of aresolving agent, or chromatography, using, for example a chiral highpressure liquid chromatography (HPLC) column. In addition, provided arealso Z- and E-forms (or cis- and trans-forms) of the compounds describedherein. Specifically, Z- and E-forms are included even if only onedesignation is named for both carbon-carbon double bonds.

Where chirality is not specified but is present, it is understood thatthe embodiment is directed to either the specific diastereomerically orenantiomerically enriched form; or a racemic or scalemic mixture of suchcompound(s).

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. A mixture of enantiomers at a ratio other than 1:1 isa “scalemic” mixture.

“Diastereoisomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other.

“Atropisomers” are stereoisomers arising due to hindered rotation abouta single bond, where the barrier to rotation about the bond is highenough to allow for isolation of individual stereoisomers. Providedincludes atropisomers of the compounds described herein.

Compositions provided herein that include a compound described herein orpharmaceutically acceptable salts, isomer, or a mixture thereof mayinclude racemic mixtures, or mixtures containing an enantiomeric excessof one enantiomer or single diastereomers or diastereomeric mixtures.All such isomeric forms of these compounds are expressly included hereinthe same as if each and every isomeric form were specifically andindividually listed.

In certain embodiments, provided are also chelates, non-covalentcomplexes, and mixtures thereof, of the compounds described herein orpharmaceutically acceptable salts, isomer, or a mixture thereof. A“chelate” is formed by the coordination of a compound to a metal ion attwo (or more) points. A “non-covalent complex” is formed by theinteraction of a compound and another molecule wherein a covalent bondis not formed between the compound and the molecule. For example,complexation can occur through van der Waals interactions, hydrogenbonding, and electrostatic interactions (also called ionic bonding).

Therapeutic Uses of the Compounds

The methods described herein may be applied to cell populations in vivoor ex vivo. “In vivo” means within a living individual, as within ananimal or human. In this context, the methods described herein may beused therapeutically in an individual. “Ex vivo” means outside of aliving individual. Examples of ex vivo cell populations include in vitrocell cultures and biological samples including fluid or tissue samplesobtained from individuals. Such samples may be obtained by methods wellknown in the art. Exemplary biological fluid samples include blood,cerebrospinal fluid, urine, and saliva. Exemplary tissue samples includetumors and biopsies thereof. In this context, the invention may be usedfor a variety of purposes, including therapeutic and experimentalpurposes. For example, the invention may be used ex vivo to determinethe optimal schedule and/or dosing of administration of an α4β7 integrininhibitor for a given indication, cell type, individual, and otherparameters. Information gleaned from such use may be used forexperimental purposes or in the clinic to set protocols for in vivotreatment. Other ex vivo uses for which the invention may be suited aredescribed below or will become apparent to those skilled in the art. Theselected compounds may be further characterized to examine the safety ortolerance dosage in human or non-human subjects. Such properties may beexamined using commonly known methods to those skilled in the art.

In some embodiments, compounds described herein, or a pharmaceuticallyacceptable salt, stereoisomer, mixture of stereoisomers, tautomer, ordeuterated analog thereof, may be used to treat subjects who have or aresuspected of having disease states, disorders, and conditions (alsocollectively referred to as “indications”) responsive or believed to beresponsive to the inhibition of α4β7 integrin activity. In someembodiments, the compounds described herein may be used to inhibit theactivity of α4β7 integrin. In some embodiments, the compounds describedherein may be used to inhibit excessive or destructive immune reactionsor growth or a proliferation of a cell, such as a cancer cell, orinhibit immunosuppression.

In some embodiments, compounds described herein, or a pharmaceuticallyacceptable salt, stereoisomer, mixture of stereoisomers, tautomer, ordeuterated analog thereof, may be used to treat subjects who have or aresuspected of having disease states, disorders, and conditions (alsocollectively referred to as “indications”) responsive or believed to beresponsive to the inhibition of α4β7 integrin activity. In someembodiments, the compounds described herein may be used to inhibit theactivity of α4β7 integrin. In some embodiments, the compounds describedherein may be used to inhibit excessive or destructive immune reactionsor growth or a proliferation of a cell, such as a cancer cell, orinhibit immunosuppression.

Methods

In some embodiments, the present disclosure provides a compounddescribed herein useful as an inhibitor of α4β7 integrin. In someembodiments, the present disclosure provides a method of treating aninflammatory disease or condition comprising administering a compounddescribed herein.

In some embodiments, the present disclosure provides a pharmaceuticalcomposition comprising a compound described herein and apharmaceutically acceptable carrier.

In some embodiments, the present disclosure provides a pharmaceuticalcomposition comprising a compound described herein and at least oneadditional therapeutic agent and at least one pharmaceuticallyacceptable excipient.

The present disclosure provides a compound described herein for use intherapy.

In another embodiment, the present disclosure provides a compounddescribed herein for use in the manufacture of a medicament for treatinga disease or condition provided herein.

In some embodiments, provided is a compound described herein useful forthe treatment of a disease or condition in a patient that is amenable totreatment by inhibiting α4β7 integrin. Diseases or conditions that maybe treated with the compounds described herein include a solid tumor,diabetes, an inflammatory disease, graft versus host disease, primarysclerosing cholangitis, HIV, an autoimmune disease, inflammatory boweldisease (IBD), alcoholic hepatitis, hepatic steatosis, nonalcoholicfatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH),systemic lupus erythematosus (SLE), and lupus nephritis.

In some embodiments, provided is a compound described herein useful forthe treatment of an inflammatory disease or condition in a patient thatis mediated, at least in part, by α4β7 integrin.

“Administering” or “administration” refers to the delivery of one ormore therapeutic agents to a patient. In some embodiments, theadministration is a monotherapy wherein a compound described herein isthe only active ingredient administered to the patient in need oftherapy. In another embodiment, the administration is co-administrationsuch that two or more therapeutic agents are delivered together duringthe course of the treatment. In some embodiments, two or moretherapeutic agents may be co-formulated into a single dosage form or“combined dosage unit”, or formulated separately and subsequentlycombined into a combined dosage unit, as is typically for intravenousadministration or oral administration as a mono or bilayer tablet orcapsule.

In some embodiments, the compound described herein is administered to ahuman patient in need thereof in an effective amount, such as, fromabout 0.1 mg to about 1000 mg per dose of said compound. In someembodiments, the effective amount is from about 0.1 mg to about 400 mgper dose. In some embodiments, the effective amount is from about 0.1 mgto about 300 mg per dose. In some embodiments, the effective amount isfrom about 0.1 mg to about 200 mg per dose. In some embodiments, theeffective amount is from about 1 mg to about 100 mg per dose. In otherembodiments, the effective amount is about 1 mg, about 3 mg, about 5 mg,about 10 mg, about 15 mg, about 18 mg, about 20 mg, about 30 mg, about40 mg, about 60 mg, about 80 mg, about 100 mg, about 200 mg, or about300 mg per dose.

In some embodiments, the compound described herein and at least oneadditional therapeutic agent is administered to a human patient in needthereof in an effective amount of each agent, independently from about0.1 mg to about 1000 mg per dose of a compound or formulation per doseper compound. In some embodiments, the effective amount of thecombination treatment of a compound described herein and an additionalcompound is independently from about 0.1 mg to about 200 mg per compoundper dose. In some embodiments, the effective amount of the combinationtreatment of a compound described herein and an additional compound isindependently from about 1 mg to about 100 mg per compound per dose. Inother embodiments, the effective amount of the combination treatment ofa compound described herein and an additional compound is for eachcomponent, about 1 mg, about 3 mg, about 5 mg, about 10 mg, about 15 mg,about 18 mg, about 20 mg, about 30 mg, about 40 mg, about 60 mg, about80 mg, about 100 mg, about 200 mg, or about 500 mg each per dose.

In some embodiments, the dose of a compound described herein and/or acombination of the dose of the compound described herein and/or the doseof an additional therapeutic agent is administered once per day, twiceper day, or thrice per day. In yet another embodiment, the dose of acompound described herein and/or the dose of an additional therapeuticagent is administered as a loading dose of from about 0.1 mg to about1000 mg per compound on the first day and each day or on alternate daysor weekly for up to a month followed by a regular regimen of a compounddescribed herein and/or one or more additional therapeutic agents ortherapies. The maintenance dose may be about 0.1 mg to about 1000 mgonce per day, twice per day, thrice per day, or weekly, for eachcomponent of a multi component drug regimen. A qualified care giver ortreating physician is aware of what dose regimen is best for aparticular patient or particular presenting conditions and will makeappropriate treating regimen decisions for that patient. Thus, inanother embodiment, the qualified caregiver is able to tailor a doseregimen of the compound described herein and/or an additionaltherapeutic agent(s) as disclosed herein to fit with the particularneeds of the patient. Thus, it will be understood that the amount of thedose of a compound described herein and the amount of the dose of anadditional therapeutic agent actually administered will usually bedetermined by a physician, in light of the relevant circumstances,including the condition(s) to be treated, the chosen route ofadministration, the actual compound (e.g., salt or free base)administered and its relative activity, the age, weight, and response ofthe individual patient, the severity of the patient's symptoms, and thelike.

Co-administration may also include administering component drugs e.g.,one on more compounds described herein and one or more additional (e.g.,a second, third, fourth or fifth) therapeutic agent(s). Such combinationof one on more compounds described herein and one or more additionaltherapeutic agent(s) may be administered simultaneously or in sequence(one after the other) within a reasonable period of time of eachadministration (e.g., about 1 minute to 24 hours) depending on thepharmacokinetic and/or pharmacodynamics properties of each agent or thecombination. Co-administration may also involve treatment with a fixedcombination wherein agents of the treatment regimen are combinable in afixed dosage or combined dosage medium e.g., solid, liquid or aerosol.In some embodiments, a kit may be used to administer the drug or drugcomponents.

Thus, some embodiments of the present disclosure is a method of treatinga disease or condition mediated, at least in part, by α4β7 integrin,comprising administering therapeutically effective amounts offormulations of one on more compounds described herein and one or moreadditional therapeutic agents, including for example, via a kit to apatient in need thereof. It will be understood that a qualified caregiver will administer or direct the administration of a therapeuticallyeffective amount of any of the compound(s) or combinations of compoundsof the present disclosure.

“Intravenous administration” is the administration of substancesdirectly into a vein, or “intravenously.” Compared with other routes ofadministration, the intravenous (IV) route is a faster way to deliverfluids and medications throughout the body. An infusion pump can allowprecise control over the flow rate and total amount of medicationdelivered. However, in cases where a change in the flow rate would nothave serious consequences, or if pumps are not available, the drip isoften left to flow simply by placing the bag above the level of thepatient and using the clamp to regulate the rate. Alternatively, a rapidinfuser can be used if the patient requires a high flow rate and the IVaccess device is of a large enough diameter to accommodate it. This iseither an inflatable cuff placed around the fluid bag to force the fluidinto the patient or a similar electrical device that may also heat thefluid being infused. When a patient requires medications only at certaintimes, intermittent infusion is used which does not require additionalfluid. It can use the same techniques as an intravenous drip (pump orgravity drip), but after the complete dose of medication has been given,the tubing is disconnected from the IV access device. Some medicationsare also given by IV push or bolus, meaning that a syringe is connectedto the IV access device and the medication is injected directly (slowly,if it might irritate the vein or cause a too-rapid effect). Once amedicine has been injected into the fluid stream of the IV tubing theremust be some means of ensuring that it gets from the tubing to thepatient. Usually this is accomplished by allowing the fluid stream toflow normally and thereby carry the medicine into the bloodstream;however, a second fluid injection is sometimes used, as a “flush”,following the injection to push the medicine into the bloodstream morequickly. Thus, in some embodiments, compound(s) or combination ofcompounds described herein may be administered by IV administrationalone or in combination with administration of certain components of thetreatment regimen by oral or parenteral routes.

“Oral administration” is a route of administration where a substance istaken through the mouth, and includes buccal, sub labial, and sublingualadministration, as well as enteral administration and that through therespiratory tract, unless made through e.g., tubing so the medication isnot in direct contact with any of the oral mucosa. Typical form for theoral administration of therapeutic agents includes the use of tablets orcapsules. Thus, in some embodiments, compound(s) or combination ofcompounds described herein may be administered by oral route alone or incombination with administration of certain components of the treatmentregimen by IV or parenteral routes.

Pharmaceutical Formulations

The compounds described herein may be administered in a pharmaceuticalformulation. Pharmaceutical formulations/compositions contemplated bythe present disclosure comprise, in addition to a carrier, the compounddescribed herein or a combination of compounds described hereinoptionally in combination with an additional therapeutic agent.

Pharmaceutical formulations/compositions contemplated by the presentdisclosure may also be intended for administration by injection andinclude aqueous solutions, oil suspensions, emulsions (with sesame oil,corn oil, cottonseed oil, or peanut oil) as well as elixirs, mannitol,dextrose, or a sterile aqueous solution, and similar pharmaceuticalvehicles. Aqueous solutions in saline are also conventionally used forinjection. Ethanol, glycerol, propylene glycol, liquid polyethyleneglycol, and the like (and suitable mixtures thereof), cyclodextrinderivatives, and vegetable oils may also be employed. The properfluidity can be maintained, for example, by the use of a coating, suchas lecithin, by the maintenance of the required particle size in thecase of dispersion and/or by the use of surfactants. The prevention ofthe action of microorganisms can be brought about by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating the componentcompound(s) in the required amount in the appropriate solvent withvarious other ingredients as enumerated above or as required, followedby filtered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum-drying and freeze-dryingtechniques which yield a powder of the active ingredient(s) plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

In making pharmaceutical compositions that comprise compound describedherein optionally in combination with an additional agent/therapy usefulfor the purpose or pharmaceutically acceptable salt thereof, the activeingredient is usually diluted by an excipient or carrier and/or enclosedor mixed with such a carrier that may be in the form of a capsule,sachet, paper or other container. When the excipient serves as adiluent, it can be a solid, semi-solid, or liquid material (as above),which acts as a vehicle, carrier or medium for the active ingredient.Thus, the compositions can be in the form of tablets, pills, powders,lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions,syrups, aerosols (as a solid or in a liquid medium), ointmentscontaining, for example, up to 20% by weight of the active compounds,soft and hard gelatin capsules, sterile injectable solutions, andsterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents.

The compositions of the disclosure may be formulated so as to providequick, sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.In some embodiments, sustained release formulations are used. Controlledrelease drug delivery systems for oral administration include osmoticpump systems and dissolutional systems containing polymer-coatedreservoirs or drug-polymer matrix formulations.

Certain compositions are preferably formulated in a unit dosage form.The term “unit dosage forms” or “combined dosage unit” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity of oneor more of the active materials (e.g., a compound described herein,optionally in combination with an additional therapeutic agentcalculated to produce the desired effect, in association with a suitablepharmaceutical excipient in for example, a tablet, capsule, ampoule orvial for injection. It will be understood, however, that the amount ofeach active agent actually administered will be determined by aphysician, in the light of the relevant circumstances, including thecondition to be treated, the chosen route of administration, the actualcompounds administered and their relative activity, the age, weight, andresponse of the individual patient, the severity of the patient'ssymptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient(s) is/are mixed with a pharmaceutical excipient to form asolid pre-formulation composition containing a homogeneous mixture of acompound of the present disclosure. When referring to thesepre-formulation compositions as homogeneous, it is meant that the activeingredient(s) are dispersed evenly throughout the composition so thatthe composition may be readily subdivided into equally effective unitdosage forms such as tablets, pills and capsules.

The tablets or pills comprising compound described herein of the presentdisclosure optionally in combination with the second agent may be coatedor otherwise compounded to provide a dosage form affording the advantageof prolonged action, or to protect from the acidic conditions of thestomach. For example, the tablet or pill can comprise an inner dosageand an outer dosage element, the latter being in the form of an envelopeover the former. In some embodiments, the inner dosage element maycomprise the compound described herein and the outer dosage element maycomprise the second or additional therapeutic agent or vice versa.Alternatively, the combined dosage unit may be side by sideconfiguration as in a capsule or tablet where one portion or half of thetablet or capsule is filled with a formulation of the compound describedherein while the other portion or half of the table or capsule comprisesthe additional therapeutic agent.

A variety of materials may be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate. One of ordinary skill in the art is aware oftechniques and materials used in the manufacture of dosages offormulations disclosed herein.

A “sustained release formulation” or “extended release formulation” is aformulation which is designed to slowly release a therapeutic agent intothe body over an extended period of time, whereas an “immediate releaseformulation” is a formulation which is designed to quickly release atherapeutic agent into the body over a shortened period of time. In somecases, the immediate release formulation may be coated such that thetherapeutic agent is only released once it reaches the desired target inthe body (e.g., the stomach). One of ordinary skill in the art is ableto develop sustained release formulations of the presently disclosedcompounds without undue experimentation. Thus in some embodiments,compound(s) or combination of compounds described herein may bedelivered via sustained released formulations alone or in combinationwith administration of certain components of the treatment regimen byoral, IV or parenteral routes.

A lyophilized formulation may also be used to administer a compounddescribed herein singly or in combination with an additional therapeuticagent. One of skill in the art is aware of how to make and uselyophilized formulations of drug substances amenable to lyophilization.

Spray-dried formulation may also be used to administer a compounddescribed herein singly or in combination with an additional therapeuticagent. One of skill in the art is aware of how to make and usespray-dried formulations of drug substances amenable to spray-drying.Other known formulation techniques may also be employed to formulate acompound or combination of compounds disclosed herein.

The compounds disclosed herein are useful for the treatment of diseasesor conditions mediated, at least in part, by α4β7 integrin. Non-limitingexamples of diseases or conditions mediated, at least in part, by α4β7integrin include, without limitation, acne, acid-induced lung injury,Addison's disease, adrenal hyperplasia, adrenocortical insufficiency,adult-onset Still's disease, adult respiratory distress syndrome (ARDS),age-related macular degeneration, aging, alcoholic hepatitis, alcoholicliver disease, allergen-induced asthma, allergic bronchopulmonary,allergic conjunctivitis, allergic contact dermatitis, allergies,allergic encephalomyelitis, allergic neuritis, allograft rejection,alopecia, alopecia areata, Alzheimer's disease, amyloidosis, amyotrophiclateral sclerosis, angina pectoris, angioedema, angiofibroma, anhidroticectodermal dysplasia-ill, anti-glomerular basement membrane disease,antigen-antibody complex mediated diseases, ankylosing spondylitis,antiphospholipid syndrome, aphthous stomatitis, appendicitis, arthritis,ascites, aspergillosis, asthma, atherosclerosis, atheroscleroticplaques, atopic dermatitis, atrophic thyroiditis, autoimmune diseases,autoimmune hemolytic anemia (immune pancytopenia, paroxysmal nocturnalhemoglobinuria), autoimmune polyendocrinopathies, autoimmunethrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediatedthrombocytopenia), autoimmune hepatitis, autoimmune thyroid disorders,autoinflammatory diseases, back pain, Bacillus anthracis infection,Bechet's disease, bee sting-induced inflammation, Behçet's syndrome,Bell's palsy, berylliosis, Blau syndrome, bone pain, bronchiolitis,bullous pemphigoid (BP) asthma, burns, bursitis, cardiac hypertrophy,carpal tunnel syndrome, Castleman's disease, catabolic disorders,cataracts, Celiac disease, cerebral aneurysm, chemical irritant-inducedinflammation, chorioretinitis, chronic atypical neutrophilic dermatosiswith lipodystrophy and elevated temperature (CANDLE) syndrome, chronicheart failure, chronic lung disease of prematurity, chronic obstructivepulmonary disease (COPD), chronic pancreatitis, chronic prostatitis,chronic recurrent multifocal osteomyelitis, cicatricial alopecia,colitis, complex regional pain syndrome, complications of organtransplantation, conjunctivitis, connective tissue disease, contactdermatitis, corneal graft neovascularization, corneal ulcer, Crohn'sdisease, cryopyrin-associated periodic syndromes, cutaneous lupuserythematosus (CLE), cryptococcosis, cystic fibrosis, deficiency of theinterleukin-1 receptor antagonist (DIRA), dermatitis, dermatitisendotoxemia, dermatomyositis, diabetic macular edema, diverticulitis,eczema, encephalitis, endometriosis, endotoxemia, eosinophilicpneumonias, epicondylitis, epidermolysis bullosa, erythema multiforme,erythroblastopenia, esophagitis, familial amyloidotic polyneuropathy,familial cold urticarial, familial Mediterranean fever, fetal growthretardation, fibromyalgia, fistulizing Crohn's disease, food allergies,giant cell arteritis, glaucoma, glioblastoma, glomerular disease,glomerular nephritis, glomerulonephritis, gluten-sensitive enteropathy,gout, gouty arthritis, graft-versus-host disease (GVHD), granulomatoushepatitis, Graves' disease, growth plate injuries, Guillain-Barresyndrome. gut diseases, hair loss, Hashimoto's thyroiditis, head injury,headache, hearing loss, heart disease, hemangioma, hemolytic anemia,hemophilic joints, Henoch-Scholein purpura, hepatitis, hepaticsteatosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholicsteatohepatitis (NASH), hereditary periodic fever syndrome, heritabledisorders of connective tissue, herpes zoster and simplex, hidradenitissuppurativa (HS), hip replacement, Hodgkin's disease, Huntington'sdisease, hyaline membrane disease, hyperactive inflammatory response,hyperammonemia, hypercalcemia, hypercholesterolemia, hypereosinophilicsyndrome (HES), hyperimmunoglobulinemia D with recurrent fever (HIDS),hypersensitivity pneumonitis, hypertropic bone formation, hypoplasticand other anemias, hypoplastic anemia, ichthyosis, idiopathicdemyelinating polyneuropathy, Idiopathic inflammatory myopathies(dermatomyositis, polymyositis), idiopathic pulmonary fibrosis,idiopathic thrombocytopenic purpura, immunoglobulin nephropathies,immune complex nephritis, immune thrombocytopenic purpura (ITP),incontinentia pigmenti (IP, Bloch-Siemens syndrome), infectiousmononucleosis, infectious diseases including viral diseases such as AIDS(HIV infection), hepatitis A, B, C, D, and E, herpes; inflammation,inflammation of the CNS, inflammatory bowel disease (IBD), inflammatorydisease of the lower respiratory tract including bronchitis or chronicobstructive pulmonary diseases, inflammatory disease of the upperrespiratory tract including the nose and sinuses such as rhinitis orsinusitis, inflammatory diseases of the respiratory tract, inflammatoryischemic event such as stroke or cardiac arrest, inflammatory lungdisease, inflammatory myopathy such as myocarditis, inflammatory liverdisease, inflammatory neuropathy, inflammatory pain, insect bite-inducedinflammation, interstitial cystitis, interstitial lung disease, iritis,irritant-induced inflammation, ischemia/reperfusion, joint replacement,juvenile arthritis, juvenile rheumatoid arthritis, keratitis, kidneyinjury caused by parasitic infections, kidney transplant rejection,leptospirosis, leukocyte adhesion deficiency, lichen sclerosus (LS),Lambert-Eaton myasthenic syndrome, Loeffler's syndrome, lupus, lupusnephritis, Lyme disease, Marfan syndrome (MFS), mast cell activationsyndrome, mastocytosis, meningitis, meningioma, mesothelioma, mixedconnective tissue disease, Muckle-Wells syndrome (urticaria deafnessamyloidosis), mucositis, multiple organ injury syndrome, multiplesclerosis, muscle wasting, muscular dystrophy, myasthenia gravis (MG),myelodysplastic syndrome, myocarditis, myositis, nasal sinusitis,necrotizing enterocolitis, neonatal onset multisystem inflammatorydisease (NOMID), neovascular glaucoma, nephrotic syndrome, neuritis,neuropathological diseases, non-allergen induced asthma, obesity, ocularallergy, optic neuritis, organ transplant rejection, Osier-Webersyndrome, osteoarthritis, osteogenesis imperfecta, osteonecrosis,osteoporosis, osteoarthritis, otitis, pachyonychia congenita, Paget'sdisease, Paget's disease of bone, pancreatitis, Parkinson's disease,pediatric rheumatology, pelvic inflammatory disease, pemphigus,pemphigus vulgaris (PV), bullous pemphigoid (BP), pericarditis, periodicfever, periodontitis, peritoneal endometriosis, pernicious anemia(Addison's disease), pertussis, PFAPA (periodic fever aphthouspharyngitis and cervical adenopathy), pharyngitis and adenitis (PFAPAsyndrome), plant irritant-induced inflammation, pneumocystis infection,pneumonia, pneumonitis, poison ivy/urushiol oil-induced inflammation,polyarthritis nodosa, polychondritis, polycystic kidney disease,polymyalgia rheumatic, giant cell arteritis, polymyositis, pouchitis,reperfusion injury and transplant rejection, primary biliary cirrhosis,primary pulmonary hypertension, primary sclerosing cholangitis (PSC),proctitis, psoriasis, psoriasis vulgaris, psoriatic arthritis, psoriaticepidermis, psychosocial stress diseases, pulmonary disease, pulmonaryfibrosis, pulmonary hypertension, pyoderma gangrenosum, pyogenicgranuloma retrolental fibroplasias, pyogenic sterile arthritis,Raynaud's syndrome, Reiter's disease, reactive arthritis, renal disease,renal graft rejection, reperfusion injury, respiratory distresssyndrome, retinal disease, retrolental fibroplasia, Reynaud's syndrome,rheumatic carditis, rheumatic diseases, rheumatic fever, rheumatoidarthritis, rhinitis, rhinitis psoriasis, rosacea, sarcoidosis,Schnitzler syndrome, scleritis, sclerosis, scleroderma, scoliosis,seborrhea, sepsis, septic shock, severe pain, Sezary syndrome, sicklecell anemia, silica-induced disease (Silicosis), Sjogren's syndrome,skin diseases, skin irritation, skin rash, skin sensitization (contactdermatitis or allergic contact dermatitis), sleep apnea, spinal cordinjury, spinal stenosis, spondyloarthropathies, sports injuries, sprainsand strains, Stevens-Johnson syndrome (SJS), stroke, subarachnoidhemorrhage, sunburn, synovial inflammation, systemic inflammatoryresponse syndrome (SIRS), systemic lupus erythematosus, systemic mastcell disease (SMCD), systemic vasculitis, systemic-onset juvenileidiopathic arthritis, temporal arteritis, tendinitis, tenosynovitis,thrombocytopenia, thyroditis, thyroiditis, tissue transplant,toxoplasmosis, trachoma, transplantation rejection, traumatic braininjury, tuberculosis, tubulointerstitial nephritis, tumor necrosisfactor (TNF) receptor associated periodic syndrome (TRAPS), type 1diabetes, type 2 diabetes, complications from type 1 or type 2 diabetes,ulcerative colitis, urticaria, uterine fibroids, uveitis, uveoretinitis,vascular restenosis, vasculitis, vasculitis (NHLBI), vitiligo, Wegener'sgranulomatosis, and Whipple's disease.

In further embodiments, the methods are provided for alleviating asymptom of a disease or disorder mediated, at least in part, by α4β7integrin. In some embodiments, the methods include identifying a mammalhaving a symptom of a disease or disorder mediated, at least in part, byα4β7 integrin, and providing to the mammal an amount of a compound asdescribed herein effective to ameliorate (i.e., lessen the severity of)the symptom.

In some embodiments, the disease or condition mediated, at least inpart, by α4β7 integrin is an inflammatory disease or LPS inducedendotoxin shock. In some embodiments, the disease is an autoimmunedisease. In particular embodiments, the autoimmune disease is systemiclupus erythematosus (SLE), myestenia gravis, rheumatoid arthritis (RA),acute disseminated encephalomyelitis, idiopathic thrombocytopenicpurpura, multiple sclerosis (MS), inflammatory bowel disease (IBD),sepsis, psoriasis, Sjoegren's syndrome, autoimmune hemolytic anemia,asthma, or chronic obstructive pulmonary disease (COPD), ankylosingspondylitis, acute gout and ankylosing spondylitis, reactive arthritis,monoarticular arthritis, osteoarthritis, gouty arthritis, juvenilearthritis, juvenile onset rheumatoid arthritis, juvenile rheumatoidarthritis or psoriatic arthritis. In other embodiments, the disease isinflammation. In yet other embodiments, the disease is excessive ordestructive immune reactions, such as asthma, rheumatoid arthritis,multiple sclerosis, chronic obstructive pulmonary disease (COPD), andlupus.

In some embodiments, the disease or condition mediated, at least inpart, by α4β7 integrin is inflammatory bowel disease (IBD). The term“inflammatory bowel disease” or “IBD” as used herein is a collectiveterm describing inflammatory disorders of the gastrointestinal tract,the most common forms of which are ulcerative colitis and Crohn'sdisease. Other forms of IBD that can be treated with the presentlydisclosed compounds, compositions and methods include diversion colitis,ischemic colitis, infectious colitis, chemical colitis, microscopiccolitis (including collagenous colitis and lymphocytic colitis),atypical colitis, pseudomembranous colitis, fulminant colitis, autisticenterocolitis, indeterminate colitis, Behçet's disease, gastroduodenalCD, jejunoileitis, ileitis, ileocolitis, Crohn's (granulomatous)colitis, irritable bowel syndrome, mucositis, radiation inducedenteritis, short bowel syndrome, celiac disease, stomach ulcers,diverticulitis, pouchitis, proctitis, and chronic diarrhea.

Treating or preventing IBD also includes ameliorating or reducing one ormore symptoms of IBD. As used herein, the term “symptoms of IBD” refersto detected symptoms such as abdominal pain, diarrhea, rectal bleeding,weight loss, fever, loss of appetite, and other more seriouscomplications, such as dehydration, anemia and malnutrition. A number ofsuch symptoms are subject to quantitative analysis (e.g. weight loss,fever, anemia, etc.). Some symptoms are readily determined from a bloodtest (e.g. anemia) or a test that detects the presence of blood (e.g.rectal bleeding). The term “wherein said symptoms are reduced” refers toa qualitative or quantitative reduction in detectable symptoms,including but not limited to a detectable impact on the rate of recoveryfrom disease (e.g. rate of weight gain). The diagnosis is typicallydetermined by way of an endoscopic observation of the mucosa, andpathologic examination of endoscopic biopsy specimens.

The course of IBD varies, and is often associated with intermittentperiods of disease remission and disease exacerbation. Various methodshave been described for characterizing disease activity and severity ofIBD as well as response to treatment in subjects having IBD. Treatmentaccording to the present methods is generally applicable to a subjecthaving IBD of any level or degree of disease activity.

In some embodiments, the disease or condition treated by theadministration of a compound of composition described herein includesacute gout and ankylosing spondylitis, allergic disorders, Alzheimer'sdisease, Amyotrophic lateral sclerosis (ALS), Amyotrophic lateralsclerosis and multiple sclerosis, atherosclerosis, bacterial infections,bone cancer pain and pain due to endometriosis, BRAF resistant melanoma,brain stem glioma or pituitary adenomas, burns, bursitis, cancer of theanal region, cancer of the endocrine system, cancer of the kidney orureter (e.g. renal cell carcinoma, and carcinoma of the renal pelvis),cancer of the penis, cancer of the small intestine, cancer of thethyroid, cancer of the urethra, cancers of the blood such as acutemyeloid leukemia, cancers of the tongue, carcinoma of the cervix,carcinoma of the endometrium, carcinoma of the fallopian tubes,carcinoma of the renal pelvis, carcinoma of the vagina or carcinoma ofthe vulva, chronic myeloid leukemia, chronic or acute leukemia, chronicpain, classic Bartter syndrome, common cold conjunctivitis, coronaryheart disease, cutaneous or intraocular melanoma, dermatitis,dysmenorrhea, eczema, endometriosis, familial adenomatous polyposis,fibromyalgia, fungal infections, gout, gynecologic tumors, uterinesarcomas, carcinoma of the fallopian tubes, headache, hemophilicarthropathy, Parkinson's disease, AIDS, herpes zoster, Hodgkin'sdisease, Huntington's, hyperprostaglandin E syndrome, influenza, iritis,juvenile arthritis, juvenile onset rheumatoid arthritis, juvenilerheumatoid arthritis, low back and neck pain, lymphocytic lymphomas,myofascial disorders, myositis, neuralgia, neurodegenerative disorderssuch as Alzheimer's disease, neuroinflammatory disorders, neuropathicpain, carcinoma of the vulva, Parkinson's disease, pediatric malignancy,pulmonary fibrosis rectal cancer, rhinitis, sarcoidosis, sarcomas ofsoft tissues, scleritis, skin cancer, solid tumors of childhood, spinalaxis tumors, sprains and strains, stomach cancer, stroke, subacute andchronic musculoskeletal pain syndromes such as bursitis, surgical ordental procedures, symptoms associated with influenza or other viralinfections, synovitis, toothache, ulcers, uterine cancer, uterinesarcomas, uveitis, vasculitis, viral infections, viral infections {e.g.influenza) and wound healing.

Criteria useful for assessment of disease activity in subjects withulcerative colitis can be found in, e.g., Truelove et al. (1955) Br MedJ 2:1041-1048.) Using these criteria, disease activity can becharacterized in a subject having IBD as mild disease activity or severedisease activity. Subjects who do not meet all the criteria for severedisease activity, and who exceed the criteria for mild disease activityare classified as having moderate disease activity.

The presently disclosed treatment methods can also be applied at anypoint in the course of the disease. In some embodiments, the methods areapplied to a subject having IBD during a time period of remission (i.e.,inactive disease). In such embodiments, the present methods providebenefit by extending the time period of remission (e.g., extending theperiod of inactive disease) or by preventing, reducing, or delaying theonset of active disease. In other embodiments, methods may be applied toa subject having IBD during a period of active disease. Such methodsprovide benefit by reducing the duration of the period of activedisease, reducing or ameliorating one or more symptoms of IBD, ortreating IBD.

Measures for determining efficacy of treatment of IBD in clinicalpractice have been described and include, for example, the following:symptom control; fistula closure; extent of corticosteroid therapyrequired; and, improvement in quality of life. Heath-related quality oflife (HRQL) can be assessed using the Inflammatory Bowel DiseaseQuestionnaire (IBDQ), which is extensively used in clinical practice toassess quality of life in a subject with IBD. (See Guyatt et al. (1989)Gastroenterology 96:804-810.) In some embodiments, the disease orcondition is immune-mediated liver injury, disease or condition.

In some embodiments, the disease or condition mediated, at least inpart, by α4β7 integrin is alcoholic hepatitis. Alcoholic hepatitis is aclinical syndrome characterized by jaundice and liver failure thatdevelops in subjects with chronic and active alcohol abuse. (SeeAkriviadis E. et. al, Ann Gastroenterol. 2016 April-June; 29(2):236-237). Alcoholic hepatitis can cause cirrhosis and fibrosis of theliver cells. Glucocorticoids, (e.g. prednisolone) and phosophodiesteraseinhibitors (e.g. pentoxifylline) can be used to treat alcoholichepatitis. The compounds herein can be used as stand-alone treatments orin combination with the current treatments for alcoholic hepatitis.

In some embodiments, the disease or condition mediated, at least inpart, by α4β7 integrin is fatty liver disease. In some embodiments, thediseases are hepatic steatosis, nonalcoholc fatty liver disease (NAFLD)and nonalcoholic steatohepatitis (NASH). The compounds herein can beused as stand-alone treatments or in combination with the currenttreatments for fatty liver diseases.

In one aspect, the present disclosure provides methods of treating orpreventing a human immunodeficiency virus (HIV) infection in a subjectin need thereof, comprising administering to the subject atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition provided herein.

In some embodiments, the disease or condition mediated, at least inpart, by α4β7 integrin is systemic lupus erythematosus (SLE), lupusnephritis, lupus-related, or other autoimmune disorders or a symptom ofSLE. Symptoms of systemic lupus erythematosus include joint pain, jointswelling, arthritis, fatigue, hair loss, mouth sores, swollen lymphnodes, sensitivity to sunlight, skin rash, headaches, numbness,tingling, seizures, vision problems, personality changes, abdominalpain, nausea, vomiting, abnormal heart rhythms, coughing up blood anddifficulty breathing, patchy skin color and Raynaud's phenomenon.

Combination Therapy

Also provided are methods of treatment in which a compound describedherein is given to a patient in combination with one or more additionalactive agents or therapy.

Thus in some embodiments, a method of treating diseases or conditionsmediated, at least in part, by α4β7 integrin and/or diseases or symptomsthat co-present or are exacerbated or triggered by the diseases orconditions mediated, at least in part, by α4β7 integrin, e.g., anallergic disorder and/or an autoimmune and/or inflammatory disease,and/or an acute inflammatory reaction, comprises administering to apatient in need thereof an effective amount of a compound describedherein optionally in combination with an additional agent (e.g., asecond, third, fourth or fifth active agent) which can be useful fortreating diseases or conditions mediated, at least in part, by α4β7, anallergic disorder and/or an autoimmune and/or inflammatory disease,and/or an acute inflammatory reaction incident to or co-presenting withdiseases or conditions mediated, at least in part, by α4β7 integrin.Treatment with the second, third, fourth or fifth active agent may beprior to, concomitant with, or following treatment with a compounddescribed herein. In some embodiments, a compound described herein iscombined with another active agent in a single dosage form. Suitabletherapeutics that may be used in combination with a compound describedherein include, but are not limited to, therapeutic agents providedherein, or a combination comprising at least one therapeutic agentprovided herein.

Included herein are methods of treatment in which a compound describedherein is administered in combination with an agent for treatment of aninflammatory disease or condition. Examples of agents for treatment ofan inflammatory disease or condition that can be used in combinationwith compounds described herein, include alpha-fetoprotein modulators;adenosine A3 receptor antagonist; adrenomedullin ligands; AKT1 geneinhibitors; antibiotics; antifungals; ASK1 inhibitors; ATPaseinhibitors; beta adrenoceptor antagonists; BTK inhibitors; calcineurininhibitors; carbohydrate metabolism modulators; cathepsin S inhibitors;CCR9 chemokine antagonists; CD233 modulators; CD29 modulators; CD3antagonists; CD40 ligand inhibitors; CD40 ligand receptor antagonists;chemokine CXC ligand inhibitors; CHST15 gene inhibitors; collagenmodulators; CSF-1 antagonists; CX3CR1 chemokine modulators; ecobiotics;eotaxin ligand inhibitors; EP4 prostanoid receptor agonists; F1F0 ATPsynthase modulators; farnesoid X receptor agonists; fecal microbiotatransplantation (FMT); fractalkine ligand inhibitors; free fatty acidreceptor 2 antagonists; GATA 3 transcription factor inhibitors;glucagon-like peptide 2 agonists; glucocorticoid agonists;Glucocorticoid receptor modulators; guanylate cyclase receptor agonists;HIF prolyl hydroxylase inhibitors; histone deacetylase inhibitors; HLAclass II antigen modulators; hypoxia inducible factor-1 stimulator;ICAM1 gene inhibitors; IL-1 beta ligand modulators; IL-12 antagonists;IL-13 antagonists; IL-18 antagonists; IL-22 agonists; IL-23 antagonists;IL-23A inhibitors; IL-6 antagonists; IL-7 receptor antagonists; IL-8receptor antagonists; integrin alpha-4/beta-1 antagonists; integrinalpha-4/beta-7 antagonists; integrin antagonists; interleukin ligandinhibitors; interleukin receptor 17A antagonists; interleukin-1 betaligands; interleukin 1 like receptor 2 inhibitors; IL-6 receptormodulators; JAK tyrosine kinase inhibitors; Jak1 tyrosine kinaseinhibitors; Jak3 tyrosine kinase inhibitors; lactoferrin stimulators;LanC like protein 2 modulators; leukocyte elastate inhibitors; leukocyteproteinase-3 inhibitors; MAdCAM inhibitors; melanin concentratinghormone (MCH-1) antagonist; melanocortin agonists; metalloprotease-9inhibitors; microbiome-targeting therapeutics; natriuretic peptidereceptor C agonists; neuregulin-4 ligands; NLPR3 inhibitors; NKG2 Dactivating NK receptor antagonists; NR1H4 receptor (FXR) agonists ormodulators; nuclear factor kappa B inhibitors; opioid receptorantagonists; OX40 ligand inhibitors; oxidoreductase inhibitors; P2X7purinoceptor modulators; PDE 4 inhibitors; Pellino homolog 1 inhibitors;PPAR alpha/delta agonists; PPAR gamma agonists; protein fimH inhibitors;P-selectin glycoprotein ligand-1 inhibitors; Ret tyrosine kinasereceptor inhibitors; RIP-1 kinase inhibitors; RIP-2 kinase inhibitors;RNA polymerase inhibitors; sphingosine 1 phosphate phosphatase 1stimulators; sphingosine-1-phosphate receptor-1 agonists;sphingosine-1-phosphate receptor-5 agonists; sphingosine-1-phosphatereceptor-1 antagonists; sphingosine-1-phosphate receptor-1 modulators;stem cell antigen-1 inhibitors; superoxide dismutase modulators; SYKinhibitors; TLR-3 antagonists; TLR-4 antagonists; Toll-like receptor 8(TLR8) inhibitors; TLR-9 agonists; TNF alpha ligand inhibitors; TNFligand inhibitors; TNF alpha ligand modulators; TNF antagonists; TPL-2inhibitors; tumor necrosis factor 14 ligand modulators; tumor necrosisfactor 15 ligand inhibitors; Tyk2 tyrosine kinase inhibitors; type IIL-1 receptor antagonists; vanilloid VR1 agonists; and zonulininhibitors, and combinations thereof.

Adenosine A3 receptor antagonists include PBF-677.

Adrenomedullin ligands include adrenomedullin.

Antibiotics include ciprofloxacin, metronidazole, vancomycin, rifaximin.

ASK1 inhibitors include GS-4997.

Alpha-fetoprotein modulators include ACT-101.

Anti-CD28 inhibitors include JNJ-3133

Beta adrenoceptor antagonists include NM-001.

BTK inhibitors include GS-4059.

Calcineurin inhibitors: include tacrolimus, and ciclosporin.

Carbohydrate metabolism modulators include ASD-003.

Cathepsin S inhibitors include VBY-129.

CCR9 chemokine antagonists include CCX-507.

CD233 modulators include GSK-2831781.

CD29 modulators include PF-06687234.

CD3 antagonists include NI-0401.

CD4 antagonists include IT-1208.

CD40 ligand inhibitors include SAR-441344, and letolizumab.

CD40 gene inhibitors include NJA-730.

CD40 ligand receptor antagonists include FFP-104, BI-655064.

Chemokine CXC ligand inhibitors include LY-3041658.

CHST15 gene inhibitors include STNM-01.

Collagen modulators include ECCS-50 (DCCT-10).

COT protein kinase inhibitors include GS-4875.

CSF-1 antagonists include JNJ-40346527 (PRV-6527), and SNDX-6352.

CX3CR1 chemokine modulators include E-6130.

Ecobiotics include SER-287.

Eotaxin ligand inhibitors include bertilimumab.

EP4 prostanoid receptor agonists include KAG-308.

F1F0 ATP synthase modulators include LYC-30937 EC.

Fractalkine ligand inhibitors include E-6011.

Free fatty acid receptor 2 antagonists include GLPG-0974.

GATA 3 transcription factor inhibitors include SB-012.

Glucagon-like peptide 2 agonists include teduglutide.

Glucocorticoid agonists include budesonide, beclomethasone dipropionate,and dexamethasone sodium phosphate.

Glucocorticoid receptor modulators/TNF ligand inhibitors includeABBV-3373.

Guanylate cyclase receptor agonists include dolcanatide.

HIF prolyl hydroxylase inhibitors include DS-1093, and AKB-4924.

HIF prolyl hydroxylase-2 inhibitors/hypoxia inducible factor-1stimulators include GB-004.

Histone deacetylase inhibitors include givinostat.

Histone deacetylase-6 inhibitors include CKD-506.

HLA class II antigen modulators include HLA class II protein modulators.

ICAM1 gene inhibitors include alicaforsen.

IL-12 antagonists include ustekinumab (IL12/IL23).

IL-13 antagonists include tralokinumab.

IL-18 antagonists include GSK-1070806

IL-22 agonists include RG-7880.

IL-23 antagonists include tildrakizumab, risankizumab (BI-655066),mirikizumab (LY-3074828), brazikumab (AMG-139), and PTG-200.

IL-23A inhibitors include guselkumab.

IL-6 antagonists include olokizumab.

IL-7 receptor antagonists include OSE-127.

IL-8 receptor antagonists include clotrimazole.

Integrin alpha-4/beta-1 antagonists include natalizumab.

Integrin alpha-4/beta-7 antagonists include etrolizumab (a4b7/aEb7),vedolizumab, carotegast methyl, TRK-170 (a4b7/a4b1), PN-10943, andPTG-100.

Integrin antagonists include E-6007.

Interleukin ligand inhibitors include bimekizumab (IL-17A/L-17F).

Interleukin receptor 17A antagonists include brodalumab.

Interleukin-1 beta ligands include K(D)PT.

Interleukin 1 like receptor 2 inhibitors include BI-655130.

IL-6 receptor modulators include olamkicept.

JAK tyrosine kinase inhibitors include tofacitinib (1/3), peficitinib(1/3), TD-3504, an TD-1473. Jak1 tyrosine kinase inhibitors include acompound disclosed in WO2008/109943. Examples of other JAK inhibitorsinclude, but are not limited to, AT9283, AZD1480, baricitinib,BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544),INCB039110, lestaurtinib, momelotinib (CYT0387), NS-018, pacritinib(SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerlytasocitinib), XL019, upadacitinib (ABT-494), filgotinib, GLPG-0555,SHR-0302, and PF-06700841 (JAK1/Tyk2).

Jak3 tyrosine kinase inhibitors include PF-06651600.

Lactoferrin stimulators include recombinant human lactoferrin (VEN-100).

LanC like protein 2 modulators include BT-11.

Leukocyte elastase inhibitors/Leukocyte proteinase-3 inhibitors includetiprelestat.

MAdCAM inhibitors include SHP-647 (PF-547659).

Melanin concentrating hormone (MCH-1) antagonists include CSTI-100.

Melanocortin agonists include ASP-3291, and PL-8177.

Metalloprotease-9 inhibitors include GS-5745.

Natriuretic peptide receptor C agonists include plecanatide.

Neuregulin-4 ligands include NRG-4.

NKG2 D activating NK receptor antagonists include JNJ-4500.

NLPR3 inhibitors include dapansutrile, BMS-986299, SB-414, MCC-950,IFM-514, JT-194, PELA-167, and NBC-6.

NR1H4 receptor (FXR) agonists or modulators include tropifexor, andGS-9674.

Nuclear factor kappa B inhibitors include Thetanix.

Opioid receptor antagonists include naltrexone, and IRT-103.

OX40 ligand inhibitors include KHK-4083.

Oxidoreductase inhibitors include olsalazine.

Pellino homolog 1 inhibitors include BBT-401.

P2X7 purinoceptor modulators include SGM-1019.

PDE 4 inhibitors include apremilast.

PPAR alpha/delta agonists include elafibranor (GFT-1007).

PPAR gamma agonists include GED-0507-34-Levo.

Protein fimH inhibitors include EB-8018.

P-selectin glycoprotein ligand-1 inhibitors include SEL-K2, AbGn-168H,and neihulizumab.

Ret tyrosine kinase receptor inhibitors include GSK-3179106.

RIP-1 kinase inhibitors include GSK-2982772.

RIP-2 kinase inhibitors include GSK-2983559.

Sphingosine 1 phosphate phosphatase 1 stimulators include etrasimod.

Sphingosine-1-phosphate receptor-1 agonists include mocravimod(KRP-203), and BMS-986166.

Sphingosine-1-phosphate receptor-1 agonists/Sphingosine-1-phosphatereceptor-5 agonists include ozanimod.

Sphingosine-1-phosphate receptor-1 antagonists include amiselimod(MT-1303).

Sphingosine-1-phosphate receptor-1 modulators include OPL-002.

Stem cell antigen-1 inhibitors include Ampion (DMI-9523).

Superoxide dismutase modulators include midismase.

Syk inhibitors include GS-9876.

TLR-3 antagonists include PRV-300.

TLR-4 antagonists include JKB-122.

Toll-like receptor 8 (TLR8) inhibitors include E-6887, IMO-4200,IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, VTX-1463,and VTX-763.

TLR-9 agonists include cobitolimod, IMO-2055, IMO-2125, lefitolimod,litenimod, MGN-1601, and PUL-042.

TNF alpha ligand inhibitors include adalimumab, certolizumab pegol,infliximab, golimumab, DLX-105, Debio-0512, HMPL-004, CYT-020-TNFQb,Hemay-007. and V-565.

TNF antagonists include AVX-470, tulinercept, and etanercept.

TPL-2 inhibitors include GS-4875.

Tumor necrosis factor 14 ligand modulators include AEVI-002.

Tumor necrosis factor 15 ligand inhibitors include PF-06480605.

Tyk2 tyrosine kinase inhibitors include PF-06826647, and BMS-986165.

Type I IL-1 receptor antagonists include anakinra.

Zonulin inhibitors include larazotide acetate.

Included herein are methods of treatment in which a compound describedherein is administered in combination with an anti-inflammatory agent.Anti-inflammatory agents include but are not limited to NSAIDs,non-specific and COX-2 specific cyclooxgenase enzyme inhibitors, goldcompounds, corticosteroids, methotrexate, tumor necrosis factor receptor(TNF) receptors antagonists, immunosuppressants and methotrexate.

Examples of NSAIDs include, but are not limited to ibuprofen,flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations ofdiclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal,piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen,sodium nabumetone, sulfasalazine, tolmetin sodium, andhydroxychloroquine. Examples of NSAIDs also include COX-2 specificinhibitors (i.e., a compound that inhibits COX-2 with an IC₅₀ that is atleast 50-fold lower than the IC₅₀ for COX-1) such as celecoxib,valdecoxib, lumiracoxib, etoricoxib and/or rofecoxib.

In a further embodiment, the anti-inflammatory agent is a salicylate.Salicylates include but are not limited to acetylsalicylic acid oraspirin, sodium salicylate, and choline and magnesium salicylates.

The anti-inflammatory agent may also be a corticosteroid. For example,the corticosteroid may be chosen from cortisone, dexamethasone,methylprednisolone, prednisolone, prednisolone sodium phosphate, andprednisone.

In some embodiments, the anti-inflammatory therapeutic agent is a goldcompound such as gold sodium thiomalate or auranofin.

In some embodiments, the anti-inflammatory agent is a metabolicinhibitor such as a dihydrofolate reductase inhibitor, such asmethotrexate or a dihydroorotate dehydrogenase inhibitor, such asleflunomide.

In some embodiments, the anti-inflammatory compound is an anti-C5monoclonal antibody (such as eculizumab or pexelizumab), a TNFantagonist, such as entanercept, or infliximab, which is an anti-TNFalpha monoclonal antibody.

Included herein are methods of treatment in which a compound describedherein, is administered in combination with an immunosuppressant. Insome embodiments, the immunosuppressant is methotrexate, leflunomide,cyclosporine, tacrolimus, azathioprine, or mycophenolate mofetil.

Included herein are methods of treatment in which a compound describedherein, is administered in combination with a class of agent fortreatment of IBD. Examples of classes of agents for treatment of IBDthat can be used in combination with a compound described herein includeASK1 inhibitors, beta adrenoceptor antagonists, BTK inhibitors,beta-glucuronidase inhibitors, bradykinin receptor modulators,calcineurin inhibitors, calcium channel inhibitors, cathepsin Sinhibitors, CCR3 chemokine antagonists, CD40 ligand receptorantagonists, chemokine CXC ligand inhibitors, CHST15 gene inhibitors,collagen modulators, CSF-1 antagonists, cyclooxygenase inhibitors,cytochrome P450 3A4 inhibitors, eotaxin ligand inhibitors, EP4prostanoid receptor agonists, fractalkine ligand inhibitors, free fattyacid receptor 2 antagonists, GATA 3 transcription factor inhibitors,glucagon-like peptide 2 agonists, glucocorticoid agonists, guanylatecyclase receptor agonists, histone deacetylase inhibitors, HLA class IIantigen modulators, IL-12 antagonists, IL-13 antagonists, IL-23antagonists, IL-6 antagonists, IL-6 receptor modulators, interleukin-7receptor modulators, IL-7 antagonists, IL-8 antagonists, integrinalpha-4/beta-1 antagonists, integrin alpha-4/beta-7 antagonists,integrin alpha-E antagonists, integrin antagonists, integrin beta-7antagonists, interleukin ligand inhibitors, interleukin receptor 17Aantagonists, interleukin-1 beta ligands, interleukin-1 beta ligandmodulators, IRAK4 inhibitors, JAK tyrosine kinase inhibitors, Jak1tyrosine kinase inhibitors, Jak3 tyrosine kinase inhibitors, LanC likeprotein 2 modulators, lipoxygenase modulators, MAdCAM inhibitors, matrixmetalloprotease inhibitors, melanocortin agonists, metalloprotease-9inhibitors, natriuretic peptide receptor C agonists, neuregulin-4ligands, NKG2 D activating NK receptor antagonists, opioid receptorantagonists, opioid receptor delta antagonists, oxidoreductaseinhibitors, P2X7 purinoceptor agonists, PDE 4 inhibitors, phagocytosisstimulating peptide modulators, potassium channel inhibitors, PPAR alphaagonists, PPAR delta agonists, PPAR gamma agonists, protein fimHinhibitors, P-selectin glycoprotein ligand-1 inhibitors, RNA polymeraseinhibitors, sphingosine 1 phosphate phosphatase 1 stimulators,sphingosine 1 phosphate phosphatase modulators, sphingosine-1-phosphatereceptor-1 agonists, sphingosine-1-phosphate receptor-1 antagonists,sphingosine-1-phosphate receptor-1 modulators, sphingosine-1-phosphatereceptor-5 modulators, STAT3 gene inhibitors, stem cell antigen-1inhibitors, superoxide dismutase modulators, superoxide dismutasestimulators, SYK inhibitors, TGF beta 1 iligand inhibitors, thymulinagonists, TLR antagonists, TLR agonists, TNF alpha ligand inhibitors,TNF antagonists, tumor necrosis factor 14 ligand modulators, type II TNFreceptor modulators, Tpl 2 inhibitors, and Zonulin inhibitors.

Included herein are methods of treatment in which a compound describedherein is administered in combination with an agent for treatment ofIBD. Examples of agents for treatment of IBD that can be used incombination with a compound described herein, or a pharmaceuticallyacceptable salt, stereoisomer, mixture of stereoisomers, tautomer, ordeuterated analog thereof, include those provided herein for thetreatment of an inflammatory disease or condition, and ABX-464,adalimumab; alicaforsen, ALLO-ASC-CD, AMG-966, anakinra, apremilast;Alequel; AMG-139; amiselimod, ASD-003, ASP-3291, AX-1505, BBT-401,balsalazide; beclomethasone dipropionate; BI-655130, BMS-986184;budesonide; CEQ-508; certolizumab; Clostridium butyricum; ChAdOx2-HAV,dexamethasone sodium phosphate, DNVX-078, etanercept; ETX-201,golimumab; GS-4997, GS-9876, GS-4875, GS-4059, infliximab; mesalazine,HLD-400, LYC-30937 EC; IONIS-JB11-2.5Rx, JNJ-64304500, JNJ-4447,naltrexone; natalizumab; neihulizumab, olsalazine; PH-46-A,propionyl-L-carnitine; PTG-100; remestemcel-L; tacrolimus; teduglutide;tofacitinib; ASP-1002; ustekinumab; vedolizumab; AVX-470; INN-108;SGM-1019; PF-06480605; PF-06651600; PF-06687234; RBX-8225, SER-287;Thetanix; TOP-1288; VBY-129; 99mTc-annexin V-128; bertilimumab; DLX-105;dolcanatide; E-6011; FFP-104; filgotinib; foralumab; GED-0507-34-Levo;givinostat; GLPG-0974; iberogast; JNJ-40346527; K(D)PT; KAG-308;KHK-4083; KRP-203; larazotide acetate; LY-3074828, midismase;olokizumab; OvaSave; P-28-GST; PF-547659; prednisolone; QBECO; RBX-2660,JKB-122; SB-012; STNM-01; Debio-0512; TRK-170; zucapsaicin; ABT-494;Ampion; BI-655066; carotegast methyl; cobitolimod; elafibranor;etrolizumab; GS-5745; HMPL-004; LP-02, ozanimod; peficitinib; RHB-104;rifaximin; tildrakizumab; tralokinumab; brodalumab; laquinimod;plecanatide; vidofludimus; and AZD-058.

Included herein are methods of treatment in which a compound describedherein is administered in combination with an agent for treatment ofgraft versus host disease. Examples of agents for treatment of graftversus host disease that can be used in combination with a compounddescribed herein include those provided herein for the treatment of aninflammatory disease or condition, and [18F]F-AraG, AM-01, AAT-IV,Allocetra, AMG-592, arsenic trioxide, ATIR-101, basiliximab, belatacept,belimumab, bortezomib, brentuximab vedotin, brimonidine, brimonidinetartrate, cannabidiol, CE-1145, ciclosporin, clazakizumab, CSL-964,CYP-001, defibrotide, dilanubicel, dornase alfa, DSM-9843, eculizumab,EDP-1066, everolimus, Furestem, GSK-1070806, ibrutinib, IMSUT-CORD,IRX-4204, KD-025, MaaT-013, milatuzumab, mizoribine, mycophenolatemofetil, MSCTC-0010, nalotimagene carmaleucel, MET-2, nilotinib,OMS-721, pacritinib, PF-05285401, PLX-1, ProTmune, QPI-1002,remestemcel-L, RGI-2001, rivogenlecleucel, saratin, SCM-CGH, sirolimus,T-allo10, telmisartan, T-Guard, TOP-1288, TZ-101, voclosporin; CCR5chemokine antagonist: PRO-140; CD40 ligand receptor antagonist:iscalimab; Complement C1s subcomponent inhibitor: sutimlimab, Cinryze,BIVV-009; B-lymphocyte antigen CD20 inhibitor: obinutuzumab; CASP9 genestimulator: rivogenlecleucel; CD3 antagonist or CD7 inhibitor: T-Guard;Complement C5a factor inhibitor: olendalizumab; Dipeptidyl peptidase IVinhibitor: begelomab; JAK1/2 tyrosine kinase inhibitor: ruxolitinib;Jak1 tyrosine kinase inhibitor: itacitinib; Interleukin-2 ligand:aldesleukin; Interleukin 22 ligand: F-652; IL-2 receptor alpha subunitinhibitor: inolimomab; IL-6 receptor agonist: PLX-1; IL-6 receptorantagonist: clazakizumab; OX40 ligand inhibitor: KY-1005; An example ofsuch OX40 inhibitor is a compound disclosed in U.S. Pat. No. 8,450,460,the entire contents of which are incorporated herein by reference;Signal transducer CD24 modulator: CD24-IgFc; Somatostatin receptoragonist: Thymoglobulin; and sphingosine-1-phosphate receptor-1 agonist:ponesimod.

Included herein are methods of treatment in which a compound describedherein is administered in combination with an agent for treatment ofprimary sclerosing cholangitis. Examples of agents for treatment ofprimary sclerosing cholangitis that can be used in combination withcompounds described herein include those provided herein for thetreatment of an inflammatory disease or condition, and BTT-1023, CM-101,Doconexent, GRI-0124, HTD-1801, HTD-2802, hymecromone, IDN-7314,NGM-282, norursodeoxycholic acid, ORBCEL-C, SCT-5-27, STP-705, farnesoidX receptor agonist: obeticholic acid, GS-9674, and MET-409; liver Xreceptor antagonist: DUR-928; and CCR5/CCR2 chemokine antagonist:cenicriviroc.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of: combination drugs for HIV, otherdrugs for treating HIV, HIV protease inhibitors, HIV non-nucleoside ornon-nucleotide inhibitors of reverse transcriptase, HIV nucleoside ornucleotide inhibitors of reverse transcriptase, HIV integraseinhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors,HIV entry inhibitors, HIV maturation inhibitors, latency reversingagents, compounds that target the HIV capsid, immune-based therapies,phosphatidylinositol 3-kinase (P3K) inhibitors, HIV antibodies,bispecific antibodies and “antibody-like” therapeutic proteins, HIV p17matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-transisomerase A modulators, protein disulfide isomerase inhibitors,complement C5a receptor antagonists, DNA methyltransferase inhibitor,HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viralinfectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nefmodulators, Hck tyrosine kinase modulators, mixed lineage kinase-3(MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors,integrin antagonists, nucleoprotein inhibitors, splicing factormodulators, COMM domain containing protein 1 modulators, HIVribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors,dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG proteininhibitors, HIV POL protein inhibitors, Complement Factor H modulators,ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclindependent kinase inhibitors, proprotein convertase PC9 stimulators, ATPdependent RNA helicase DDX3X inhibitors, reverse transcriptase primingcomplex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokineticenhancers, HIV gene therapy, and HIV vaccines, or a pharmaceuticallyacceptable salt of any of the foregoing, or any combinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of HIV protease inhibiting compounds,HIV non-nucleoside inhibitors of reverse transcriptase, HIVnon-nucleotide inhibitors of reverse transcriptase, HIV nucleosideinhibitors of reverse transcriptase, HIV nucleotide inhibitors ofreverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerizationinhibitors, pharmacokinetic enhancers, and other drugs for treating HIV,or a pharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the one or more additional therapeutic agent is animmune modulating agent, e.g., an immunostimulant or animmunosuppressant. In certain other embodiments, an immune modulatingagent is an agent capable of altering the function of immunecheckpoints, including the CTLA-4, LAG-3, B7-H3, B7-H4, Tim3, BTLA, KIR,A2aR, CD200 and/or PD-1 pathways. In other embodiments, the immunemodulating agent is immune checkpoint modulating agents. Exemplaryimmune checkpoint modulating agents include anti-CTLA-4 antibody (e.g.,ipilimumab), anti-LAG-3 antibody, anti-B7-H3 antibody, anti-B7-H4antibody, anti-Tim3 antibody, anti-BTLA antibody, anti-KIR antibody,anti-A2aR antibody, anti CD200 antibody, anti-PD-1 antibody, anti-PD-L1antibody, anti-CD28 antibody, anti-CD80 or -CD86 antibody, anti-B7RP1antibody, anti-B7-H3 antibody, anti-HVEM antibody, anti-CD137 or -CD137Lantibody, anti-OX40 or —OX40L antibody, anti-CD40 or -CD40L antibody,anti-GAL9 antibody, anti-IL-10 antibody and A2aR drug. For certain suchimmune pathway gene products, the use of either antagonists or agonistsof such gene products is contemplated, as are small molecule modulatorsof such gene products. In some embodiments, immune modulating agentsinclude those agents capable of altering the function of mediators incytokine mediated signaling pathways.

In some embodiments, a compound as disclosed herein (e.g., a compounddescribed herein may be combined with one or more (e.g., one, two,three, four, one or two, one to three, or one to four) additionaltherapeutic agents in any dosage amount of the compound described herein(e.g., from 10 mg to 1000 mg of compound).

A compound described herein may be combined with the agents providedherein in any dosage amount of the compound (e.g., from 50 mg to 500 mgof compound) the same as if each combination of dosages werespecifically and individually listed.

In some embodiments, provided are kits comprising a pharmaceuticalcomposition comprising a compound described herein or a compounddescribed herein and at least one additional therapeutic agent, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier. In some embodiments, kitscomprising a compound disclosed herein, or a pharmaceutically acceptablesalt, stereoisomer, mixture of stereoisomers, tautomer, or deuteratedanalog thereof, in combination with one or more (e.g., one, two, three,four, one or two, or one to three, or one to four) additionaltherapeutic agents are provided. Any pharmaceutical composition providedin the present disclosure may be used in the kits, the same as if eachand every composition were specifically and individually listed for usein a kit. In some embodiments, the kit comprises instructions for use inthe treatment of an inflammatory disease or condition. In someembodiments, the instructions in the kit are directed to use of thepharmaceutical composition for the treatment of IBD.

LIST OF ABBREVIATIONS AND ACRONYMS

Abbreviation Meaning % Percent ° C. Degree Celsius Ac Acetyl AcOH Aceticacid ACN/CH₃CN/MeCN Acetonitrile ADME Absorption, distribution,metabolism and excretion AlBN 2,2′-Azobis(2-methylpropionitrile) Aq.Aqueous ASK Apoptosis signal- regulating kinase Bicarb Bicarbonate BnBenzyl BOC/Boc Tert-butyloxycarbonyl Bpin Pinacolborane br Broad CASChemical Abstract Service CNS Central nervous system COPD Chronicobstructive pulmonary disease CREST Calcinosis, Raynaud’s syndrome,esophageal CVP Cyclophosphamide, vincristine, prednisone d Doublet D/dDeuterium DAST Diethylaminosulfur trifluoride DABCO ®1,4-Diazabicyclo[2.2.2]octane DCC N,N′-Dicyclohexylcarbodiimide DCEDichloroethane DCM Dichloromethane/methylene chloride dd Doublet ofdoublets DIEA N,N-Diisopropylethylamine DMA N,N-Dimethylacetamide DMAP4-Dimethylaminopyridine DME Dimethoxy ethane DMF Dimethylformamide DMPKDrug metabolism and pharmacokinetics DMSO Dimethylsulfoxide DPPADiphenylphosphoryl azide EC₅₀ The half maximal effective concentrationequiv/eq Equivalents EA Ethyl acetate Et₂O Diethyl ether EtOAc/AcOEtEthyl acetate EtOH Ethanol F Fahrenheit FBS Fetal bovine serum g GramsGp Glycoprotein h/hr Hours HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- hex Hexanes HPLC High pressure liquidchromatography Hz Hertz IL Interleukin IUPAC International Union of Pureand Applied Chemistry J Coupling constant (MHz) JAK Janus kinase Kg/kgKilogram L Liter LCMS/LC-MS Liquid chromatography- mass spectrometryLHMDS Lithium hexamethyl disilazide LiMg-TMP2,2,6,6-Tetramethylpiperidinyl- magnesium chloride M Molar m multipletM+ Mass peak M+H Mass peak plus hydrogen m-CPBA Meta-Chloroperbenzoicacid Me Methyl Me₂N Dimethylamine MeI Methyl Iodide MeOH Methanol MeOTsMethyl Tosylate mg Milligram MHz Megahertz min/m Minute ml/mL MillilitermM Millimolar mmol Millimole mol Mole MS Mass spectroscopy MS Multiplesclerosis MsCl Methanesulfonyl chloride MTBE Methyl tert-Butyl ether M/ZMass/Charge N Normal NADH Nicotinamide adenine dinucleotide in reducedform NaOH Sodium hydroxide NBS N-Bromosuccinimide ng Nanograms NISN-Iodosuccinimide nM Nanomolar NMR Nuclear magnetic resonance ONOvernight PEG Polyethylene glycol PET Positron emission tomography PhPhenyl PhMe Toluene PhNO₂ Nitrobenzene PhNTf₂ N-Phenyl triflamide pHExpressing the acidity or alkalinity of a solution prep Preparative RARheumatoid arthritis Rf Retention factor RPM Revolutions per minute RT/rRoom temperature s Second s Singlet sat. Saturated SFC Super-criticalfluid chromatography SLE Systemic lupus erythematosus SPECTSingle-photon emission computed tomography SYK Spleen tyrosine kinase tTriplet TBACl Tetrabutylammonium chloride TBS / TBDMSTert-butyldimethylsilyl tBuOH Tert-butanol TCA Trichloroacetic acidTEA/NEt₃ Triethylamine temp. Temperature TES Triethylsilane TFATrifluoroacetic acid TFAA Trifluoroacetic acid anhydride THFTetrahydrofuran TLC Thin-layer chromatography TMP Tetramethyl piperidineTMS Trimethylsilyl Tol Toluene TPL2 Tumor Progression Locus 2 KinaseTrityl Triphenylmethyl Vac Vacuum w/v Weight/volume w/w Weight/weight δChemical shift (ppm) μg Microgram μL/μl Microliter μM Micromolar μmMicrometer μmol Micromole

Synthesis

The compounds of the disclosure may be prepared using methods disclosedherein and routine modifications thereof which will be apparent giventhe disclosure herein and methods well known in the art. Conventionaland well-known synthetic methods may be used in addition to theteachings herein. The synthesis of typical compounds of formula (I),e.g., compounds having structures described by one or more of formula(I), or other formulas or compounds disclosed herein, or apharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, tautomer, or deuterated analog thereof, may beaccomplished as described in the following examples.

General Schemes

Typical embodiments of compounds in accordance with the presentdisclosure may be synthesized using the general reaction schemes and/orexamples described below. It will be apparent given the descriptionherein that the general schemes may be altered by substitution of thestarting materials with other materials having similar structures toresult in products that are correspondingly different. Descriptions ofsyntheses follow to provide numerous examples of how the startingmaterials may vary to provide corresponding products. Starting materialsare typically obtained from commercial sources or synthesized usingpublished methods for synthesizing compounds which are embodiments ofthe present disclosure, inspection of the structure of the compound tobe synthesized will provide the identity of each substituent group. Theidentity of the final product will generally render apparent theidentity of the necessary starting materials by a simple process ofinspection, given the examples herein.

General Scheme 1 describes a general route that was used to preparecompounds of Formula (I). From Intermediate AA that has hydroxyl orhalogen group as Q, and halogen group as X, amino acid esters (AA2) canbe prepared under a variety of conditions (eg. Schollkopf, Maruoka,etc). After appropriate protection of the free amine with protectinggroups (PG), eg. Trityl, Boc, etc., AA2 was converted to a boronic acidor boronic ester (AA3) under standard conditions (eg. Miyaura). R¹ wasintroduced under a variety of cross coupling conditions to give AA4.After removal of the amine protecting group (PG) under appropriateconditions, the amine was coupled with acids to provide AA5.

In some embodiments, AA4 is prepared as outlined in General Scheme 2which describes another general route to prepare compounds of Formula(I). From Intermediate AA6 that has a halogen group as Q, and an aminogroup, several chemical steps such as urea formation and ring closurecan prepare the R¹ group on AA7. Amino acid esters (AA4) can be preparedfrom AA7 under a variety of conditions (eg. Schollkopf, Maruoka, etc).After appropriate removal of the amine protecting group (PG) underappropriate conditions, the amine was coupled with acids to provideheterocyclic compounds AA5.

Intermediate A

Synthesis of tert-butyl 4-bromo-2,6-difluorobenzoate (A1): To a stirredsolution of 4-bromo-2,6-difluorobenzoic acid (5 g, 21.1 mmol) in DCM (50mL) and tert-butyl alcohol (50 mL) was added di-tert-butyl dicarbonate(9.2 g, 42.2 mol) followed by 4-dimethylaminopyridine (0.8 g, 6.3 mmol).The reaction mixture was allowed to stir at RT for 12 h. The reactionmixture was concentrated under reduced pressure, dissolved in EA (100mL) and washed with a 10% aqueous solution of citric acid (100 mL). Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄, andconcentrated under reduced pressure to afford crude material. Thismaterial was suspended in hexanes, the solid was filtered off and thefiltrate was evaporated under reduced pressure to afford compound A1.

Synthesis of tert-butyl(R)-2,6-difluoro-4-((1,1,1-trifluorobutan-2-yl)amino)benzoate (A2): To astirred suspension of A1 (250 mg, 0.55 mmol),(R)-1,1,1-trifluorobutan-2-amine (85 mg, 0.67 mmol), and cesiumcarbonate (904 mg, 2.8 mmol) in toluene (5 mL) was added XPhos Pd G3 (42mg, 0.06 mmol). The reaction mixture was sparged with nitrogen and thenheated to 90° C. for 12 h. The mixture was cooled to RT and diluted withEA (50 mL). The resultant suspension was filtered through a pad ofcelite, and the filtrate was evaporated under reduced pressure to affordcompound A2.

Synthesis of(R)-2,6-difluoro-4-((1,1,1-trifluorobutan-2-yl)amino)benzoic acid (A):To a stirred solution of A2 (188 mg, 0.55 mmol) in DCM (1 mL) was addedTFA (1 mL). The reaction mixture was allowed to stir at RT for 20 mins.The reaction mixture was concentrated under reduced pressure to affordcrude material. This material was purified by silica gel columnchromatography and eluted EA in hexane to afford intermediate A. MS(m/z) 284.1 [M+H]⁺.

Intermediate B

Synthesis of (R)-2,6-difluoro-4-(3-(trifluoromethyl)morpholino)benzoicacid (B): To a 150 mL pressure vessel containing a stir bar was addedmethyl 4-bromo-2,6-difluorobenzoate (700 mg, 1.8 mmol), RuPhos (169 mg,0.36 mmol), tBuBrettPhos Pd G3 (155 mg, 0.18 mmol), Cs₂CO₃ (2.95 g, 9.1mmol), (R)-3-(trifluoromethyl)morpholine (416 mg, 2.7 mmol) and toluene(18 mL). The reaction vessel was then sealed and heated at 90° C.overnight. The reaction mixture was cooled to RT and filtered over a padof Celite, rinsed with EA and the filtrate was evaporated to drynessunder reduced pressure. The material was purified by silica gelchromatography using EA in Hexane as eluent. To this material was addedTHF (6 mL) and aqueous LiOH (6.2 mL, 1.0 M). The reaction mixture wasstirred at 60° C. for 20 hrs. The reaction mixture was cooled to RT andacidified with 1.0 M HCl before extracting with EA. Organic layers werecombined and dried over Na₂SO₄. The solvent was removed under reducedpressure to afford intermediate B.

Intermediate C

Synthesis of(R)-2-fluoro-6-methyl-4-(3-(trifluoromethyl)morpholino)benzoic acid (C):The title compound was prepared according to the method presented forthe synthesis of intermediate B starting with methyl4-bromo-2-fluoro-6-methylbenzoate.

Intermediate D

Synthesis of(R)-2-fluoro-6-methyl-4-((1,1,1-trifluorobutan-2-yl)amino)benzoic acid(D): The title compound was prepared according to the method presentedfor the synthesis of intermediate A starting with tert-butyl4-bromo-2-fluoro-6-methylbenzoate.

Intermediate E

Synthesis of tert-butyl(R)-2,3,6-trifluoro-4-((1,1,1-trifluorobutan-2-yl)amino)benzoate (E1):To a stirred suspension of tert-butyl 4-bromo-2,3,6-trifluorobenzoate(250 mg, 0.55 mmol), (R)-1,1,1-trifluorobutan-2-amine (85 mg, 0.67mmol), and cesium carbonate (904 mg, 2.8 mmol) in toluene (5 mL) wasadded XPhos Pd G3 (42 mg, 0.06 mmol). The reaction mixture was spargedwith nitrogen and then heated to 90° C. for 2 h. The mixture was cooledto RT and diluted with EA (50 mL). The resultant suspension was filteredthrough a pad of celite, and the filtrate was evaporated under reducedpressure to afford compound E1.

Synthesis of(R)-2,3,6-trifluoro-4-((1,1,1-trifluorobutan-2-yl)amino)benzoic acid(E): To a stirred solution of E1 (188 mg, 0.55 mmol) in DCM (1 mL) wasadded TFA (1 mL). The reaction mixture was allowed to stir at RT for 20mins. The reaction mixture was concentrated under reduced pressure toafford crude material. This material was purified by silica gel columnchromatography and eluted EA in hexane to afford intermediate E.

Intermediate F

Synthesis of methyl(R)-2,6-difluoro-4-((1,1,1-trifluorobutan-2-yl)amino)benzoate (F1): To asolution of intermediate A (300 mg, 1.06 mmol) in MeOH (3 mL) and DCM (5mL) was added TMS diazomethane (1.06 mL, 2.12 mmol). The reactionmixture was allowed to stir for 45 min at RT. Water was added and theorganic layer was washed with brine, dried over Na₂SO₄, and concentratedin vacuo to provide F1 without further purification.

Synthesis of methyl(R)-4-(cyclopropyl(1,1,1-trifluorobutan-2-yl)amino)-2,6-difluorobenzoate(F2): To F1 (307 mg, 0.67 mmol) in dioxane was added Cs₂CO₃ (656 mg, 2mmol) and Pd-176 (56 mg, 0.067 mmol). The reaction mixture was purgedwith N₂, and then cyclopropyl bromide (406 mg, 3.36 mmol) was added. Thereaction was heated to 95° C. ON. The reaction mixture was filteredthrough celite, concentrated in vacuo, and purified by silica gelchromatography eluting with Hex/EA 0-60% to give F2.

Synthesis of(R)-4-(cyclopropyl(1,1,1-trifluorobutan-2-yl)amino)-2,6-difluorobenzoicacid (F): To F2 (360 mg, 1.07 mmol) in THF was added 1.0 M LiOH (5 mL).The reaction was allowed to stir ON at 40° C. 2.0 M HCl was added (20mL) and extracted 3 times w/EA. Combined organics were washed with brineand concentrated in vacuo to give intermediate F without furtherpurification.

Intermediate G

Synthesis of 5-iodo-1,6-dimethyl-4-(trifluoromethyl)pyridin-2(1H)-one(G): A solution of 6-methyl-4-(trifluoromethyl)pyridin-2(1H)-one (1.26g, 7.11 mmol), TFA (16.0 g, 140 mmol), and TFAA (3.2 g, 15 mmol) in DME(3.80 mL) was heated at 60° C. for 5 min, followed by the addition ofNIS (2.04 g, 9.0 mmol). The mixture was then heated at 60° C. for anadditional 12 h, after which the solvent was removed under reducedpressure and the residue was dissolved in EA, washed with water, andwashed with sat. aq. NaHCO₃. The organic layer was concentrated underreduced pressure and the crude product was suspended in DME (3.80 mL).To this mixture was added K₂CO₃ (0.98 g, 7.0 mmol) and Mel (1.0 g, 7.0mmol) and the mixture was heated at 95° C. for 2 h. Upon completion, thereaction was diluted with EA, and the solid was filtered off and washedwith EA. The filtrate was concentrated under reduced pressure and thecrude product was purified using flash chromatography eluting with EA inhexanes (25% to 100%) to afford intermediate G.

Intermediate H

Synthesis of 1,4-dimethyl-5-(trifluoromethyl)pyridin-2(1H)-one (H1): Toa stirred solution of 4-methyl-5-(trifluoromethyl)pyridin-2(1H)-one (100mg, 0.056 mmol) in DMF was added NaH (25 mg, 0.62 mmol) and the reactionmixture was allowed to stir for 30 min at which time the bubblingceased. The reaction mixture was cooled to 0° C. and methylp-toluenesulfonate (116 mg, 0.062 mmol) was added dropwise. After 4 hrsthe reaction mixture was allowed to warm to RT, concentrated underreduced pressure, and purified on silica gel chromatography eluting withHex/EA 0-100% to afford the title compound.

Synthesis of 3-iodo-1,4-dimethyl-5-(trifluoromethyl)pyridin-2(1H)-one(H): To a stirred solution of H1 (0.72 g, 4 mmol) in neat TFA (16 mL)was added TFAA (1.6 g, 8 mmol). The reaction mixture was heated to 100°C. for 5 min in a sealed vial, followed by the addition of NIS (1.08 g,5 mmol) and further heating at 60° C. for 3 hrs. The reaction mixturewas cooled and the TFA removed under reduced pressure. The residue wasdissolved in EA and washed with sat. sodium bicarbonate then brine. Theorganic layer was filtered then concentrated to give intermediate Gwithout further purification.

Intermediate I

Synthesis of(2S,5R)-2-(4-bromo-3-methylbenzyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine(11): To a solution of (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine(1.36 g, 7.39 mmol) in THF (28.0 mL) at −78° C. was added a solution ofn-BuLi in hexanes (4.62 g, 7.96 mmol). The mixture was stirred at −78°C. for 20 min, followed by the drop-wise addition of a solution of1-bromo-4-(bromomethyl)-2-methylbenzene (1.5 g, 5.68 mmol) in THF (37mL). The reaction was stirred for 40 min at −78° C., and quenched withwater (10 mL). The cold bath was removed and the reaction was allowed towarm to RT, and extracted with EA, washed with brine, dried over Na₂SO₄and concentrated under reduced pressure to afford the crude material.The crude product was purified using flash chromatography eluting withEA in hexanes (10% to 100%) to afford compound 11.

Synthesis of(2S,5S)-2-isopropyl-3,6-dimethoxy-5-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-2,5-dihydropyrazine(12): To a solution of compound 11 (297 mg, 0.809 mmol) in DMA (5.40 mL)was added bis(pinacolato)diboron (262 mg, 1.03 mmol) and KOAc (238 mg,2.42 mmol) and the mixture was purged with nitrogen gas for 6 min.CataCXium A Pd G3 (29.5 mg, 0.04 mmol) was added and the mixture washeated at 90° C. for 1 h. Upon completion, the reaction was quenchedwith water, extracted with EA, washed with brine, dried over Na₂SO₄, andconcentrated under concentrated under reduced pressure to affordcompound 12 which was used without further purification.

Synthesis of3-(4-(((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)methyl)-2-methylphenyl)-1,6-dimethyl-4-(trifluoromethyl)pyridin-2(1H)-one(13): To a solution of compound 12 (130 mg, 0.157 mmol),3-iodo-1,6-dimethyl-4-(trifluoromethyl)pyridin-2(1H)-one (65.0 mg, 0.204mmol) in DME (1.50 mL) was added a 1 M aqueous solution of K₃PO4 (117mg, 0.550 mmol) and the mixture was purged with nitrogen gas for 6 min.XPhos Pd G3 (13.0 mg, 0.016 mmol) was then added and the mixture waspurged with nitrogen gas for an additional 3 min and heated thermally at77° C. for 45 min. The solvent was then removed under reduced pressure,and the mixture was dissolved in EA, washed with H₂O, dried over Na₂SO₄and concentrated under reduced pressure to afford the crude material.The crude material was purified using flash chromatography eluting withEA in hexanes (20% to 100%) and then MeOH in EA (0% to 35%) to afford13.

Synthesis of methyl(S)-2-amino-3-(4-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)-3-methylphenyl)propanoate(1): To a solution of compound 13 (185 mg, 0.387 mmol) in ACN (13 mL)was added an aqueous solution of 2 M HCl (67.6 mg, 1.16 mmol) and themixture was stirred at rt for 3 h. Upon completion, the solvent wasremoved under reduced pressure and the crude material was purified usingflash chromatography eluting with EA in hexanes (0% to 100%), then MeOHin DCM (0% to 35%) to afford intermediate I.

Intermediate J

Synthesis of(2S,5R)-2-(4-bromo-3-fluorobenzyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine(J1): The title compound was prepared according to the method presentedfor the synthesis of intermediate I1 starting with1-bromo-4-(bromomethyl)-2-fluorobenzene.

Synthesis of(2S,5R)-2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine(J2): The title compound was prepared according to the method presentedfor the synthesis of intermediate I2 starting with J1.

Synthesis of3-(2-fluoro-4-(((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)methyl)phenyl)-1,6-dimethyl-4-(trifluoromethyl)pyridin-2(1H)-one(J3): The title compound was prepared according to the method presentedfor the synthesis of I3 starting with compound J2.

Synthesis of methyl(S)-2-amino-3-(4-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)-3-fluorophenyl)propanoate(J): The title compound was prepared according to the method presentedfor the synthesis of intermediate I starting with compound J3.

Intermediate K

Synthesis of methyl 3-(3-(5-bromopyridin-2-yl)ureido)isonicotinate (K1):To methyl 3-aminoisonicotinate (21.5 g, 141 mmol, 1.00 eq) in DCM (430.0mL) was added DIEA (36.5 g, 282 mmol, 49.2 mL, 2.00 eq). The mixture wasdegassed and purge with N₂ three times, then cooled 0° C. Triphosgene(14.69 g, 49.5 mmol, 0.35 eq) dissolved in DCM (90.0 mL) at 0° C. wasadded slowly. The mixture was allowed to stir for 2 h at 0° C. thenconcentrated in vacuo. MeCN (150.0 mL) and 5-bromopyridin-2-amine (24.4g, 141 mmol, 1.00 eq) were added to the mixture and it was allowed tostir for 2 h at 65° C. After cooling to RT, the solids were filtered offand collected to give K1.

Synthesis of3-(5-bromopyridin-2-yl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione(K2): K1, without further purification, was dissolved in MeCN (430 mL)and allowed to stir for 16 h at 65° C. K₂CO₃ was added (19.5 g, 141.4mmol, 1.00 eq), followed by MeOTs (39.4 g, 211.7 mmol, 1.5 eq). Theresulting mixture was allowed to stir for 8 h at 65° C. EA (500 mL) andwater (500 mL) were added. The organic layer was removed and the aqueousphase extracted with additional EA (500 mL). The combined organic layerwas washed with brine (500 mL), dried over Na₂SO₄, and concentrated invacuo. TBME was added to create a slurry and the resulting solids werecollected on filter paper to give K2.

Synthesis of methyl(S)-2-((tert-butoxycarbonyl)amino)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoate(K3): Zn (7.85 g, 120.0 mmol, 4.00 eq) was added to a round bottom flaskand heated with a heat-gun at 110° C. for 10 minutes under vacuum. Aftercooling to RT, DMA (130 mL) and TMSCl (1.63 g, 15.0 mmol, 1.90 mL, 0.50eq) was added and allowed to stir at 70° C. for 1 h. Methyl(R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (19.7 g, 60.0 mmol,2.00 eq) dissolved in DMA (40 mL) was added and allowed to stir at 50°C. for 1 h. After cooling to 30° C., the zinc reagent was added dropwiseto a previously degassed mixture of K2 (10.0 g, 30.0 mmol, 1.00 eq) andPd(PPhs)₂C2 (6.32 g, 9.01 mmol, 0.30 eq) in DMA (130.0 mL). The reactionmixture was allowed to stir at 80° C. for 3 h. After cooling to RT, EA(200 mL) and water (500 mL) was added. The organic layer was separatedand the aqueous layer washed with EA (200 mL). The combined organiclayers were washed with brine (200 mL), dried over Na₂SO₄, andconcentrated in vacuo. The material was purified by silica gel columnchromatography using EA/hexanes to give K3.

Synthesis of methyl(S)-2-amino-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoate(K): The title compound was prepared according to the method presentedfor the synthesis of intermediate I starting with compound K3.

Intermediate L

Synthesis of cyclopropyl O-benzyl-N-(tert-butoxycarbonyl)-L-serinate(L1): To O-benzyl-N-(tert-butoxycarbonyl)-L-serine (20 g, 68 mmol) inDCM (135 mL) was added DMAP (8.27 g, 68 mmol), EDCl (25.96 g, 135 mmol)and cyclopropanol (39 g, 677 mmol). The mixture was stirred for 4 h,diluted with EA (500 mL) and washed with water (500 mL) and 0.5 N citricacid (2×500 mL). The organic layer was evaporated and the residuechromatographed silica gel eluting with 50% EA in hexanes to provide L1.

Synthesis of cyclopropyl (tert-butoxycarbonyl)-L-serinate (L2): To L1(5.5 g, 16 mmol) in EA (10 mL) was added palladium on charcoal (3.5 g,5% Pd). The contents were agitated on a Parr shaker under 50 PSI ofhydrogen gas for 3 hours at RT. The mixture was filtered, washed with EAand solvents were evaporated providing L2, which was used in the nextstep without further purification.

Synthesis of cyclopropyl(R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (L3): To L2 (2.8 g11.4 mmol) in DCM was added iodine (3.2 g 13 mmol, 1.1 eq), imidazole(0.855 g, 13 mmol, 1.1 eq), and PPh₃ (2.96 g, 12 mmol 1.05 eq) and themixture allowed to stir for 2h. Solvents were removed in vacuo and theresidue was chromatographed on silica gel eluting with EA in hexanes(0-20%) to provide L3.

Synthesis of cyclopropyl(S)-2-((tert-butoxycarbonyl)amino)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoate(L4): Zinc (1.27 g, 19.5 mmol, 20-30 mesh granular) was added to a flamedried round bottom flask vial containing a stir bar. DMF (4.2 mL) andTMSCl (0.49 mL, 3.8 mmol) were added and the mixture was stirred for 30minutes. A syringe was used to decant the supernatant and the activatedzinc was further washed with DMF (2×1.3 mL). L3 (2.985 g, 8.4 mmol, 2eq) was then added in DMF (4.9 mL) dropwise at a rate so as to keep theresultant exotherm below 50° C. and then stirred for 30 minutes. Theiodozinc reagent was then taken up via syringe and added to a secondflask containing intermediate K2 (1.4 g, 4.2 mmol, 1 eq), palladiumacetate (0.094 g, 0.42 mmol, 0.1 eq), Xphos (0.24 g, 0.5 mmol, 0.12 eq)and DMF (7.8 mL) and the reaction mixture was allowed to stir at 45° C.for 3 days. The mixture was diluted with EA, filtered through celite,solvents were removed in vacuo and chromatographed on silica gel elutingwith methanol in DCM (0-10% methanol) to provide L4.

Synthesis of cyclopropyl(S)-2-amino-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoate(L): To L4 (1.8 g, 3.7 mmol) was added DCM (12 mL) and TFA (12 mL). Thereaction was allowed to stir for 2 hours, and then concentrated in vacuoto give intermediate L.

Intermediate M

Synthesis of methyl 3-(3-(6-iodopyridin-3-yl)ureido)isonicotinate (M1):To a 500 mL RB flask was added 6-iodopyridin-3-amine (5.0 g, 22.7 mmol,1 eq.), 4-(methoxycarbonyl)nicotinic acid (4.57 g, 29.5 mmol, 1.3 eq.),(trifluoromethyl)benzene (46.0 mL) and triethylamine (4.76 mL, 34.1mmol, 1.5 eq.). The reaction mixture was heated to 50° C. for 10 mins.After which time, diphenylphosphoryl azide (6.37 mL, 29.5 mmol, 1.3 eq.)was added dropwise to the reaction mixture. The reaction was allowed tostir for 60 min. The reaction mixture was cooled to RT and partitionedbetween ethyl acetate and water (200 ml each). Organics were separatedand washed with brine (100 mL), dried over sodium sulfate, filtered andconcentrated under vacuum. Crude purified by column chromatography onsilica gel using methanol in DCM 0-20% as the eluant to afford the titlecompound (M1).

Synthesis of3-(6-iodopyridin-3-yl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione(M2): The title compound was prepared according to the method presentedfor the synthesis of intermediate K2 starting with M1.

Synthesis of methyl(S)-2-((tert-butoxycarbonyl)amino)-3-(5-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-2-yl)propanoate(M3): The title compound was prepared according to the method presentedfor the synthesis of intermediate K3 starting with M2.

Synthesis of methyl(S)-2-amino-3-(5-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-2-yl)propanoate(M): The title compound was prepared according to the method presentedfor the synthesis of intermediate K starting with M3.

Intermediate N

Synthesis of methyl(S)-3-(3-(4-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)phenyl)ureido)isonicotinate(N1): The title compound was prepared according to the method presentedfor the synthesis of intermediate M1 starting with methyl(S)-3-(4-aminophenyl)-2-((tert-butoxycarbonyl)amino)propanoate.

Synthesis of methyl(S)-2-((tert-butoxycarbonyl)amino)-3-(4-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)phenyl)propanoate(N2): The title compound was prepared according to the method presentedfor the synthesis of intermediate M2 starting with N1.

Synthesis of methyl(S)-2-amino-3-(4-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)phenyl)propanoate(N): The title compound was prepared according to the method presentedfor the synthesis of intermediate L starting with N2.

Intermediate O

Synthesis of methyl 3-(3-(4-iodo-2-methoxyphenyl)ureido)isonicotinate(O1): The title compound was prepared according to the method presentedfor the synthesis of intermediate M1 starting with4-iodo-2-methoxyaniline.

Synthesis of3-(4-iodo-2-methoxyphenyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione(O2): The title compound was prepared according to the method presentedfor the synthesis of intermediate M2 starting with O1.

Synthesis of methyl(S)-2-((tert-butoxycarbonyl)amino)-3-(3-methoxy-4-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)phenyl)propanoate(O3): The title compound was prepared according to the method presentedfor the synthesis of M3 starting with O2.

Synthesis of methyl(S)-2-amino-3-(3-methoxy-4-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)phenyl)propanoate(0): The title compound was prepared according to the method presentedfor the synthesis of intermediate M starting with O3.

Intermediate P

Synthesis of(R)-2-chloro-6-fluoro-4-(3-(trifluoromethyl)morpholino)benzoic acid acid(P): To a 150 mL pressure vessel containing a stir bar was added methyl4-bromo-2,6-difluorobenzoate (200 mg, 0.52 mmol), RuPhos (48 mg, 0.10mmol), tBuBrettPhos Pd G3 (44 mg, 0.052 mmol), Cs2CO3 (844 mg, 2.6mmol), (R)-3-(trifluoromethyl)morpholine (198 mg, 1.0 mmol) and toluene(6 mL). The reaction vessel was then sealed and heated at 90° C.overnight. The reaction mixture was cooled to RT and filtered over a padof Celite, rinsed with EtOAc and the filtrate was evaporated to drynessunder reduced pressure. The material was purified by silica gelchromatography using EtOAc in Hexane as eluent to a yellow oil. To thismaterial was added THF (2.6 mL) and aqueous LiOH (0.78 mL, 1.0 M). Thereaction mixture was stirred at 40° C. for 20 hrs and 50° C. for anadditional 4 hours. The reaction mixture was cooled to RT and acidifiedwith 1.0 M HCl before extracting with EtOAc. Organic layers werecombined and dried over Na2SO4. The solvent was removed under reducedpressure to afford P.

Intermediate Q

Synthesis of(S)-4-(3-(2,2-difluoroethyl)morpholino)-2-fluoro-6-methylbenzoic acid(Q): To a 150 mL pressure vessel containing a stir bar was added methyl4-bromo-2-fluoro-6-methylbenzoate (700 mg, 1.8 mmol), RuPhos (169 mg,0.36 mmol), tBuBrettPhos Pd G3 (155 mg, 0.18 mmol), Cs2CO3 (2.95 g, 9.1mmol), (S)-3-(2,2-difluoroethyl)morpholine (416 mg, 2.7 mmol) andtoluene (18 mL). The reaction vessel was then sealed and heated at 90°C. overnight. The reaction mixture was cooled to RT and filtered over apad of Celite, rinsed with EA and the filtrate was evaporated to drynessunder reduced pressure. The material was purified by silica gelchromatography using EA in Hexane as eluent. To this material was addedTHF (6 mL) and aqueous LiOH (6.2 mL, 1.0 M). The reaction mixture wasstirred at 60° C. for 20 hrs. The reaction mixture was cooled to RT andacidified with 1.0 M HCl before extracting with EA. Organic layers werecombined and dried over Na₂SO₄. The solvent was removed under reducedpressure to afford Q.

Intermediate R

Synthesis of methyl(S)-4-(3-(4-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)phenyl)ureido)-5,6-dihydro-2H-pyran-3-carboxylate(R1): To a solution of methyl 4-amino-5,6-dihydro-2H-pyran-3-carboxylate(114 mg, 0.725 mmol) in dichloromethane (4 mL) was added 20% phosgene intoluene (0.352 mL, 0.67 mmol), and the reaction was allowed to stir atroom temperature for 30 minutes. It was cooled to 0° C., then Hunig'sbase (0.237 mL, 1.36 mmol) was added, followed by methyl(S)-3-(4-aminophenyl)-2-((tert-butoxycarbonyl)amino)propanoate (100 mg,0.34 mmol). The reaction was allowed to warm to room temperature andstir for 16 hours. It was diluted with ethyl acetate and was washed with10% citric acid, saturated sodium bicarbonate, and saturated sodiumchloride solutions. It was dried over anhydrous sodium sulfate,filtered, and concentrated. It was purified via flash chromatrography(5-100% linear gradient of ethyl acetate/hexanes) to yield R1.

Synthesis of methyl(S)-2-((tert-butoxycarbonyl)amino)-3-(4-(2,4-dioxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-d]pyrimidin-3(4H)-yl)phenyl)propanoate(R2): To a solution of R1 (107 mg, 0.224 mmol) in anhydrous methanol(2.8 mL) was added anhydrous potassium carbonate (155 mg, 1.12 mmol),and the reaction was allowed to stir for 20 minutes. It was quenched bythe addition of 10% citric acid in water. Additional water was added toprecipitate the product, which was collected via filtration to yield R2.

Synthesis of methyl(S)-2-((tert-butoxycarbonyl)amino)-3-(4-(1-methyl-2,4-dioxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-d]pyrimidin-3(4H)-yl)phenyl)propanoate(R3): To a solution of R2 (47 mg, 0.11 mmol) in N,N-dimethylformamide(0.36 mL) was added anhydrous potassium carbonate (15 mg, 0.11 mmol) andmethyl tosylate (16 μL, 0.11 mmol), and the reaction was allowed to stirfor 4 hours. Water was added to precipitate the product, and the solidswere collected to yield R3.

Synthesis of methyl(S)-2-amino-3-(4-(1-methyl-2,4-dioxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-d]pyrimidin-3(4H)-yl)phenyl)propanoate(R): To R3 (37 mg, 0.08 mmol) in ethyl acetate (0.7 mL) was added 4Mhydrogen chloride in dioxane (0.2 mL, 0.8 mmol), and the reaction wasallowed to stir for 16 hours. It was concentrated to yield R.

Intermediate S

Synthesis of ethyl 5-amino-3,6-dihydro-2H-pyran-4-carboxylate (S1): To asolution of ethyl 3-oxotetrahydro-2H-pyran-4-carboxylate (2.0 g, 12mmol) in methanol (71 mL) was added ammonium acetate (4.57 g, 59 mmol),and the reaction was stirred at room temperature for 3 hours. It wasconcentrated, dissolved in dichloromethane, and washed with water andsaturated sodium chloride. It was dried over anhydrous sodium sulfate,filtered, and concentrated to yield S1.

Synthesis of methyl(S)-2-amino-3-(4-(1-methyl-2,4-dioxo-1,2,4,5,6,8-hexahydro-3H-pyrano[3,4-d]pyrimidin-3-yl)phenyl)propanoate(S): The title compound was prepared according to the method presentedfor the synthesis of intermediate R starting with S1.

Intermediate T

Synthesis of methyl(S)-2-amino-3-(4-(1-methyl-2,4-dioxo-1,2,4,5,6,7-hexahydro-3H-cyclopenta[d]pyrimidin-3-yl)phenyl)propanoate(T): The title compound was prepared according to the method presentedfor the synthesis of intermediate R starting with methyl2-aminocyclopent-1-ene-1-carboxylate.

Intermediate U

Synthesis of methyl(S)-2-amino-3-(4-(1-methyl-2,4-dioxo-1,2,5,7-tetrahydrofuro[3,4-d]pyrimidin-3(4H)-yl)phenyl)propanoate(U): The title compound was prepared according to the method presentedfor the synthesis of intermediate R starting with methyl4-amino-2,5-dihydrofuran-3-carboxylate.

Intermediate V

Synthesis of ethyl(S)-2-amino-3-(6-(1-methyl-2,4-dioxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-d]pyrimidin-3(4H)-yl)pyridin-3-yl)propanoate(V): The title compound was prepared according to the method presentedfor the synthesis of intermediate R starting with methyl4-amino-5,6-dihydro-2H-pyran-3-carboxylate.

Intermediate W

Synthesis of methyl 4-amino-2,5-dihydrofuran-3-carboxylate (W1): Thetitle compound was prepared according to the method presented for thesynthesis of intermediate S1 starting with methyl4-oxotetrahydrofuran-3-carboxylate.

Synthesis of methyl4-(3-(4-iodophenyl)ureido)-2,5-dihydrofuran-3-carboxylate (W2): Thetitle compound was prepared according to the method presented for thesynthesis of intermediate S2 starting with W1.

Synthesis of methyl(S)-2-amino-3-(4-(1-methyl-2,4-dioxo-1,2,5,7-tetrahydrofuro[3,4-d]pyrimidin-3(4H)-yl)phenyl)propanoate(W): The title compound was prepared according to the method presentedfor the synthesis of intermediate O starting with W2 in place of O1.

Example 1

Synthesis of methyl(S)-2-((tert-butoxycarbonyl)amino)-3-(4-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)phenyl)propanoate(1A): A solution of(S)-(4-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)phenyl)boronicacid (100 mg, 0.310 mmol) and3-iodo-1,6-dimethyl-4-(trifluoromethyl)pyridin-2(1H)-one (124 mg, 0.390mmol) in DME (1.6 mL) was purged with nitrogen gas for 5 min. To thismixture was added XPhos Pd G3 (26.0 mg, 0.031 mmol) and a 1 M aqueoussolution of K₃PO4 (230 mg, 1.00 mmol), and the reaction was purged withnitrogen gas for an addition 5 min. The mixture was then heated at 77°C. for 7 min under stirring. Upon completion, the solvent was removedunder reduced pressure and the mixture was dissolved in EA, washed withwater, dried over Na₂SO₄, and concentrated under reduced pressure toafford the crude material. The crude product was purified using flashchromatography eluting with EA in hexanes (20% to 80%) to affordcompound 1A.

Synthesis of methyl(S)-2-amino-3-(4-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)phenyl)propanoate(1B): To a solution of compound 1A (98.0 mg, 0.210 mmol) in EA (1.1 mL)was added a 4M solution of HCl in dioxane (76.2 mg, 2.10 mmol) and themixture was stirred at rt for 2 h. Upon completion, the solvent wasremoved under reduced pressure and the crude product 1B was used in thenext step without further purification.

Synthesis of(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(4-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)phenyl)propanoicacid (1): To a solution of compound 1B (85.0 mg, 0.210 mmol),intermediate A (65.0 mg, 0.231 mmol), and DIEA (163 mg, 1.26 mmol) inDMF (2.1 mL) was added HATU (96.0 mg, 0.252 mmol) and the mixture wasstirred at rt for 2 h. Upon completion, the mixture was diluted with EA,washed with water, dried over Na₂SO₄, and concentrated under reducedpressure to afford the crude material. The crude product was purifiedusing flash chromatography eluting with EA in hexanes (12% to 100%) toafford the ester. To a solution of the ester (91.0 mg, 0.144 mmol) inTHF (4.80 mL) was added a 1 M aqueous solution of LiOH (10.0 mg, 0.432mmol), and the mixture was stirred at rt for 40 min. Upon completion,the mixture was acidified with TFA, and the volatiles were removed underreduced pressure. The crude material was dissolved in DMSO andchromatographed on C-18 modified silica gel eluting with acetonitrile inwater (0.4% TFA) to afford compound 1. MS (m/z) 620.1 [M+H]+. 1H NMR(400 MHz, DMSO-d6) δ 8.68 (d, J=7.7 Hz, 1H), 7.28 (d, J=8.1 Hz, 2H),7.06 (d, J=8.2 Hz, 2H), 6.76 (d, J=10.4 Hz, 1H), 6.50 (s, 1H), 6.45 (d,J=11.4 Hz, 2H), 4.58-4.50 (m, 1H), 4.37-4.26 (m, 1H), 3.48 (s, 3H), 3.13(dd, J=14.1, 5.8 Hz, 1H), 2.97 (dd, J=13.7, 10.1 Hz, 1H), 2.47 (s, 3H),1.81-1.74 (m, 1H), 1.59-1.48 (m, 1H), 0.93 (t, J=7.5 Hz, 3H).

Example 2

Synthesis of methyl(S)-2-((tert-butoxycarbonyl)amino)-3-(4-(1,2-dimethyl-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridin-3-yl)phenyl)propanoate(2A): A solution of(S)-(4-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)phenyl)boronicacid (200 mg, 0.619 mmol) and intermediate G (247 mg, 0.780 mmol) in DME(3.0 mL) was purged with nitrogen gas for 5 min. To this mixture wasadded XPhos Pd G3 (52.0 mg, 0.062 mmol) and a 1 M aqueous solution ofK₃PO4 (460 mg, 2.0 mmol), and the reaction was purged with nitrogen gasfor an additional 5 min. The mixture was then heated at 90° C. for 10min while stirring, after which the solvent was removed under reducedpressure. The mixture was dissolved in EA, washed with water, dried overNa₂SO₄, and concentrated under reduced pressure to afford the crudematerial. The crude product was purified using flash chromatographyeluting with EA in hexanes (20% to 80%) to afford compound 2A.

Synthesis of methyl(S)-2-amino-3-(4-(1,2-dimethyl-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridin-3-yl)phenyl)propanoate(2B): The title compound was prepared according to the method presentedfor the synthesis of 1B starting with 2A.

Synthesis of(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(4-(1,2-dimethyl-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridin-3-yl)phenyl)propanoicacid (2): The title compound was prepared according to the methodpresented for the synthesis of 1 starting with 2B and intermediate A. MS(m/z) 620.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J=8.1 Hz, 1H),7.35-7.30 (m, 2H), 7.09 (t, J=7.4 Hz, 2H), 6.74 (d, J=10.9 Hz, 1H), 6.73(s, 1H), 6.43 (d, J=11.3 Hz, 2H), 4.66-4.57 (m, 1H), 4.37-4.24 (m, 1H),3.54 (s, 3H), 3.18 (dd, J=14.1, 4.4 Hz, 1H), 2.94 (dd, J=14.3, 10.2 Hz,1H), 2.03 (s, 3H), 1.80 (s, 1H), 1.58-1.47 (m, 1H), 0.93 (t, J=7.2 Hz,3H).

Example 3

Synthesis of(S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(4-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)phenyl)propanoicacid (3): The title compound was prepared according to the methodpresented for the synthesis of 1 using intermediate 1B and intermediateB. MS (m/z) 648.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J=7.9 Hz,1H), 7.29 (d, J=8.1 Hz, 2H), 7.06 (d, J=8.0 Hz, 2H), 6.76 (d, J=11.6 Hz,2H), 6.49 (s, 2H), 4.91 (m, 1H), 4.57 (m, 1H), 4.16 (d, J=12.7 Hz, 1H),3.96 (dd, J=11.5, 3.8 Hz, 1H), 3.78-3.70 (m, 1H), 3.56 (td, J=11.6, 2.9Hz, 1H), 3.48 (s, 3H), 3.43 (d, J=12.9 Hz, 1H), 3.24 (t, J=12.2 Hz, 1H),3.15 (dd, J=14.2, 4.7 Hz, 1H), 2.99 (dd, J=14.1, 9.8 Hz, 1H), 2.47 (s,3H).

Example 4

Synthesis of methyl(S)-2-((tert-butoxycarbonyl)amino)-3-(4-(1,4-dimethyl-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)phenyl)propanoate(4A): A solution of(S)-(4-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)phenyl)boronicacid (100 mg, 0.310 mmol) and intermediate H (124 mg, 0.390 mmol) in DME(1.6 mL) was purged with nitrogen gas for 5 min. To this mixture wasadded XPhos Pd G3 (26.0 mg, 0.031 mmol) and a 1 M aqueous solution ofK₃PO₄ (230 mg, 1.00 mmol), and the reaction was purged with nitrogen gasfor an additional 5 min. The mixture was then heated at 77° C. for 7 minunder stirring. Upon completion, the solvent was removed under reducedpressure and the mixture was dissolved in EA, washed with water, driedover Na₂SO₄, and concentrated under reduced pressure to afford the crudematerial. The crude product was purified using flash chromatographyeluting with EA in hexanes (20% to 100%) to afford compound 4A.

Synthesis of methyl(S)-2-amino-3-(4-(1,4-dimethyl-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)phenyl)propanoate(4B):The title compound was prepared according to the method presented forthe synthesis of 1B starting with compound 4A.

Synthesis of(S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(4-(1,4-dimethyl-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)phenyl)propanoicacid (4): The title compound was prepared according to the methodpresented for the synthesis of 1 starting with compound 4B andintermediate B. MS (m/z) 648.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.82(d, J=8.0 Hz, 1H), 8.30 (s, 1H), 7.32 (d, J=8.1 Hz, 2H), 7.09 (d, J=8.2Hz, 2H), 6.76 (d, J=11.6 Hz, 2H), 4.90 (td, J=8.5, 3.2 Hz, 1H),4.62-4.55 (m, 1H), 4.16 (d, J=12.7 Hz, 1H), 3.98-3.91 (m, 1H), 3.76-3.71(m, 1H), 3.59-3.52 (m, 1H), 3.49 (s, 3H), 3.42 (d, J=12.3 Hz, 1H),3.29-3.23 (m, 1H), 3.17 (dd, J=14.0, 4.6 Hz, 1H), 2.98 (dd, J=13.9, 10.1Hz, 1H), 2.00 (s, 3H).

Example 5

Synthesis of(S)-3-(4-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)-3-methylphenyl)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)propanoicacid (5): The title compound was prepared according to the methodpresented for the synthesis of 1 starting with intermediate I andintermediate C. MS (m/z) 658.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.71(dd, J=8.0, 4.0 Hz, 1H), 7.17 (d, J=12.1 Hz, 1H), 7.10 (t, J=8.5 Hz,1H), 6.89-6.83 (m, 1H), 6.69 (d, J=14.1 Hz, 1H), 6.65 (s, 1H), 6.51 (s,1H), 4.90-4.79 (m, 1H), 4.68-4.55 (m, 1H), 4.14 (d, J=12.6 Hz, 1H), 3.94(dd, J=11.2, 3.2 Hz, 1H), 3.73 (d, J=11.9 Hz, 1H), 3.59-3.51 (m, 1H),3.50 (s, 3H), 3.35 (d, J=11.5 Hz, 1H), 3.27 (d, J=12.8 Hz, 1H), 3.13(dd, J=14.2, 3.9 Hz, 1H), 2.97-2.89 (m, 1H), 2.49 (s, 3H), 2.04 (d,J=1.6 Hz, 3H), 1.97 (d, J=4.0 Hz, 3H).

Example 6

Synthesis of(S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(4-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)-3-fluorophenyl)propanoicacid (6): The title compound was prepared according to the methodpresented for the synthesis of 1 starting with intermediate J andintermediate B. MS (m/z) 666.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.87(dd, J=7.9, 2.4 Hz, 1H), 7.19-7.03 (m, 2H), 6.77 (d, J=8.1 Hz, 2H), 6.54(s, 1H), 4.97-4.86 (m, 1H), 4.63-4.54 (m, 1H), 4.16 (d, J=12.7 Hz, 1H),3.95 (dd, J=11.3, 3.5 Hz, 1H), 3.74 (d, J=14.9 Hz, 1H), 3.56 (td,J=11.9, 2.8 Hz, 1H), 3.50 (s, 3H), 3.43 (d, J=13.9 Hz, 1H), 3.22 (ddd,J=31.6, 12.8, 4.0 Hz, 2H), 3.00 (t, J=13.3 Hz, 1H).

Example 7

Synthesis of(2S,5R)-2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine(7A): To a solution of (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine(361 mg, 1.96 mmol) in THF (9.80 mL) at −78° C. was added a solution ofn-BuLi in hexanes (2.11 g, 2.11 mmol). The mixture was stirred at −78°C. for 20 min, followed by the drop-wise addition of a solution of2-(4-(bromomethyl)-2-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(500 mg, 1.51 mmol) in THF (7.50 mL). The reaction was stirred for 40min at −78° C., and quenched with water. The cold bath was removed andthe reaction was allowed to warm to rt, and extracted with EA, washedwith brine, dried over Na₂SO₄ and concentrated under reduced pressure toafford compound 7A which was used without further purification.

Synthesis of3-(2-chloro-4-(((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)methyl)phenyl)-1,5,6-trimethylpyrazin-2(1H)-one(7B): To a solution of compound 7A (200 mg, 0.276 mmol),3-chloro-1,5,6-trimethylpyrazin-2(1H)-one (47.6 mg, 0.276 mmol) in DME(2.3 mL) was added a 1 M aqueous solution of K₃PO₄ (342 mg, 0.1.61 mmol)and the mixture was purged with nitrogen gas for 6 min. XPhos Pd G3(11.7 mg, 0.014 mmol) was then added and the mixture was purged withnitrogen gas for an additional 4 min and heated at 90° C. for 30 min.The solvent was then removed under reduced pressure, and the mixture wasdissolved in EA, washed with water, dried over Na₂SO₄ and concentratedunder reduced pressure to afford the crude material. The crude productwas purified using flash chromatography eluting with EA in hexanes (20%to 100%) and then MeOH in EA (0% to 25%) to afford compound 7B.

Synthesis of methyl(S)-2-amino-3-(3-chloro-4-(4,5,6-trimethyl-3-oxo-3,4-dihydropyrazin-2-yl)phenyl)propanoate(7C): The title compound was prepared according to the method presentedfor the synthesis of intermediate J starting with compound 7B.

Synthesis of(S)-3-(3-chloro-4-(4,5,6-trimethyl-3-oxo-3,4-dihydropyrazin-2-yl)phenyl)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)propanoicacid (7): The title compound was prepared according to the methodpresented for the synthesis of 1 using 7C and intermediate C. MS (m/z)625.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J=7.8 Hz, 1H), 7.42(s, 1H), 7.29 (s, 2H), 6.73-6.63 (m, 2H), 4.90-4.79 (m, 1H), 4.64-4.56(m, 1H), 4.14 (d, J=7.9 Hz, 1H), 3.95 (d, J=11.7 Hz, 1H), 3.73 (d,J=13.9 Hz, 1H), 3.56 (d, J=12.2 Hz, 1H), 3.52 (s, 3H), 3.36 (d, J=11.3Hz, 1H), 3.27 (d, J=11.9 Hz, 1H), 3.18 (d, J=11.2 Hz, 1H), 3.03-2.93 (m,1H), 2.37 (s, 3H), 2.30 (s, 3H), 2.09 (s, 3H).

Example 8

Synthesis of methyl(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoate(8): The title compound was prepared according to the method presentedfor the synthesis of 1 using intermediate K and intermediate A. MS (m/z)621.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.93 (d, J=7.6Hz, 1H), 8.56 (d, J=5.0 Hz, 1H), 8.47 (d, J=2.3 Hz, 1H), 7.96-7.85 (m,2H), 7.40 (d, J=8.1 Hz, 1H), 6.81 (d, J=9.4 Hz, 1H), 6.46 (d, J=11.6 Hz,2H), 4.72-4.56 (m, 1H), 4.31 (d, J=10.0 Hz, 1H), 3.20 (dd, J=14.2, 5.1Hz, 1H), 3.16-2.99 (m, 2H), 2.67 (d, J=0.7 Hz, 2H), 1.76 (ddd, J=13.7,7.3, 3.3 Hz, 1H), 1.52 (ddd, J=13.8, 10.5, 7.2 Hz, 1H), 1.32-1.21 (m,6H), 1.09 (d, J=0.7 Hz, 2H), 0.91 (t, J=7.3 Hz, 3H).

Example 9

Synthesis of(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoicacid (9): To 8 (12.5 mg, 0.02 mmol) dissolved in THF was added 1.0 MLiOH (0.04 mL, 0.04 mmol) and the mixture was allowed to stir for 1 hrat RT. 4.0 M HCl in dioxane (0.1 mL, 0.4 mmol) was then added and themixture was allowed to stir ON. The reaction mixture was concentrated,filtered, and purified via reverse phase HPLC (MeCN/H₂O) to afford 9.

Example 10

Synthesis of methyl(S)-2-(2-fluoro-6-methyl-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoate(10): The title compound was prepared according to the method presentedfor the synthesis of 1 using intermediate K and intermediate D. MS (m/z)617.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.81 (d, J=7.8Hz, 1H), 8.57 (dd, J=5.1, 1.8 Hz, 1H), 8.49 (s, 1H), 8.16 (s, 2H), 7.92(dd, J=12.9, 6.5 Hz, 2H), 7.42 (d, J=8.1 Hz, 1H), 6.40 (d, J=7.4 Hz,2H), 6.32 (d, J=9.3 Hz, 1H), 4.72 (d, J=6.2 Hz, 1H), 4.20 (s, 1H), 3.68(d, J=2.0 Hz, 3H), 3.32 (d, J=1.9 Hz, 4H), 3.24 (dd, J=14.9, 4.6 Hz,1H), 3.19-3.01 (m, 4H), 2.00 (s, 3H), 1.75 (d, J=10.1 Hz, 1H), 1.55 (d,J=15.8 Hz, 1H), 0.93 (t, J=7.3 Hz, 3H).

Example 11

Synthesis of(S)-2-(2-fluoro-6-methyl-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoicacid (11): The title compound was prepared according to the methodpresented for the synthesis of Example 9 starting with 10. MS (m/z)603.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.00 (d, J=1.9 Hz, 1H), 8.67(d, J=8.1 Hz, 1H), 8.62-8.52 (m, 1H), 8.50 (s, 1H), 8.02-7.80 (m, 2H),7.41 (dd, J=8.2, 2.0 Hz, 1H), 6.53-6.34 (m, 3H), 6.30 (d, J=9.2 Hz, 1H),5.76 (d, J=1.8 Hz, 1H), 4.65 (d, J=11.1 Hz, 1H), 4.03 (d, J=7.0 Hz, 1H),3.61 (s, 3H), 3.26 (d, J=13.9 Hz, 1H), 3.03 (t, J=12.6 Hz, 1H), 2.00 (d,J=2.3 Hz, 4H), 1.89-1.63 (m, 2H), 1.52 (dd, J=14.8, 8.1 Hz, 1H), 0.93(t, J=7.4 Hz, 3H).

Example 12

Synthesis of methyl(S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoate(12): The title compound was prepared according to the method presentedfor the synthesis of 1 using intermediate K and intermediate B. MS (m/z)649.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.09 (d, J=7.6 Hz, 1H), 9.00(s, 1H), 8.57 (dd, J=5.0, 1.5 Hz, 1H), 8.50 (d, J=2.0 Hz, 1H), 8.01-7.80(m, 2H), 7.42 (d, J=8.0 Hz, 1H), 6.79 (d, J=11.8 Hz, 2H), 5.09-4.81 (m,1H), 4.70 (td, J=9.0, 5.7 Hz, 1H), 4.17 (d, J=12.7 Hz, 1H), 4.07-3.88(m, 1H), 3.75 (d, J=12.9 Hz, 1H), 3.67 (d, J=1.6 Hz, 3H), 3.61 (d, J=1.6Hz, 3H), 3.58-3.51 (m, 1H), 3.44 (d, J=12.7 Hz, 1H), 3.29-3.19 (m, 2H),3.12 (dd, J=14.2, 9.9 Hz, 1H).

Example 13

Synthesis of(S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoicacid (13): The title compound was prepared according to the methodpresented for the synthesis of Example 9 starting with 12. MS (m/z)635.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.95 (d, J=7.9Hz, 1H), 8.57 (d, J=5.0 Hz, 1H), 8.50 (d, J=2.3 Hz, 1H), 7.96-7.85 (m,2H), 7.41 (d, J=8.1 Hz, 1H), 6.78 (d, J=11.6 Hz, 2H), 4.92 (s, 1H),4.70-4.55 (m, 1H), 4.16 (d, J=12.7 Hz, 1H), 3.96 (dd, J=11.3, 3.9 Hz,1H), 3.74 (d, J=12.6 Hz, 1H), 3.61 (s, 3H), 3.55 (d, J=10.6 Hz, 1H),3.44 (d, J=12.5 Hz, 1H), 3.25 (dd, J=14.3, 4.6 Hz, 2H), 3.08 (dd,J=14.3, 10.0 Hz, 1H).

Example 14

Synthesis of methyl(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoate(14): The title compound was prepared according to the method presentedfor the synthesis of 1 using intermediate K and intermediate C. MS (m/z)644.8 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.93 (d, J=7.9Hz, 1H), 8.57 (dd, J=5.0, 1.6 Hz, 1H), 8.50 (s, 1H), 7.93 (dd, J=16.9,6.6 Hz, 2H), 7.42 (d, J=8.1 Hz, 1H), 6.87-6.48 (m, 2H), 4.93-4.69 (m,2H), 4.15 (d, J=12.7 Hz, 2H), 3.97 (s, 12H), 3.77-3.71 (m, 1H), 3.69 (d,J=1.7 Hz, 3H), 3.61 (d, J=1.7 Hz, 3H), 3.59-3.48 (m, 1H), 3.36 (d,J=12.4 Hz, 1H), 3.26 (dd, J=14.1, 4.9 Hz, 2H), 3.14-3.01 (m, 1H), 2.06(s, 3H).

Example 15

Synthesis of(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoicacid (15): The title compound was prepared according to the methodpresented for the synthesis of Example 9 starting with 14. MS (m/z)631.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.79 (d, J=8.1Hz, 1H), 8.57 (d, J=5.0 Hz, 1H), 8.50 (s, 1H), 7.95 (d, J=8.3 Hz, 1H),7.90 (d, J=5.1 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 6.75-6.61 (m, 2H), 4.85(d, J=9.6 Hz, 1H), 4.69 (d, J=8.4 Hz, 1H), 4.15 (d, J=12.6 Hz, 1H),4.07-3.90 (m, 1H), 3.73 (d, J=12.6 Hz, 1H), 3.61 (s, 3H), 3.59-3.49 (m,1H), 3.43-3.19 (m, 3H), 3.13-2.95 (m, 1H), 2.04 (s, 3H).

Example 16

Synthesis of methyl(S)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)-2-(2,3,6-trifluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)propanoate (16): The title compound was prepared according to the methodpresented for the synthesis of 1 using intermediate K and intermediateE. MS (m/z) 639.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J=7.8 Hz,1H), 9.00 (s, 1H), 8.60-8.54 (m, 1H), 8.49 (s, 1H), 7.92 (d, J=8.3 Hz,2H), 7.48-7.35 (m, 1H), 6.99-6.78 (m, 1H), 6.73 (d, J=9.3 Hz, 1H),4.77-4.66 (m, 1H), 4.44-4.34 (m, 1H), 3.67 (s, 3H), 3.61 (s, 3H),3.29-3.19 (m, 1H), 3.16-3.04 (m, 1H), 1.77 (q, J=7.3 Hz, 2H), 0.93 (t,J=6.8 Hz, 3H).

Example 17

Synthesis of(S)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)-2-(2,3,6-trifluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)propanoicacid (17): The title compound was prepared according to the methodpresented for the synthesis of Example 9 starting with 16. MS (m/z)625.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.02-8.91 (m, 2H), 8.57 (d,J=5.4 Hz, 1H), 8.49 (s, 1H), 7.98-7.87 (m, 2H), 7.44-7.36 (m, 1H),6.94-6.80 (m, 1H), 6.71 (d, J=9.2 Hz, 1H), 4.64 (s, 1H), 3.61 (s, 3H),3.26 (d, J=14.1 Hz, 1H), 3.15-2.95 (m, 1H), 1.77 (d, J=8.4 Hz, 2H), 0.93(t, J=7.1 Hz, 3H).

Example 18

Synthesis of methyl(S)-2-(4-(cyclopropyl((R)-1,1,1-trifluorobutan-2-yl)amino)-2,6-difluorobenzamido)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoate(18): The title compound was prepared according to the method presentedfor the synthesis of 1 using intermediate K and intermediate F. MS (m/z)661.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J=7.6 Hz, 1H), 9.00(s, 1H), 8.57 (d, J=5.0 Hz, 1H), 8.52-8.45 (m, 1H), 7.96-7.87 (m, 2H),7.42 (dd, J=8.1, 0.7 Hz, 1H), 6.68 (d, J=12.1 Hz, 2H), 5.68 (ddd,J=22.3, 10.1, 4.9 Hz, 1H), 5.25-5.15 (m, 2H), 4.81 (s, 1H), 4.69 (ddd,J=10.1, 7.6, 5.1 Hz, 1H), 4.01 (s, 2H), 3.67 (s, 3H), 3.61 (s, 3H), 3.23(dd, J=14.2, 5.1 Hz, 1H), 3.09 (dd, J=14.2, 10.0 Hz, 1H), 1.92 (ddd,J=14.3, 10.4, 7.1 Hz, 1H), 1.78 (dtd, J=13.8, 7.0, 3.8 Hz, 1H), 0.87 (t,J=7.3 Hz, 3H).

Example 19

Synthesis of(S)-2-(4-(cyclopropyl((R)-1,1,1-trifluorobutan-2-yl)amino)-2,6-difluorobenzamido)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoicacid (19): The title compound was prepared according to the methodpresented for the synthesis of Example 9 starting with 18. MS (m/z)647.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 13.23-12.44 (s, 1H), 9.00 (s,1H), 8.91 (d, J=7.9 Hz, 1H), 8.57 (d, J=4.9 Hz, 1H), 8.50 (d, J=2.3 Hz,1H), 7.97-7.86 (m, 2H), 7.45-7.38 (m, 1H), 6.67 (d, J=12.0 Hz, 2H),5.78-5.59 (m, 1H), 5.28-5.12 (m, 2H), 4.81 (s, 1H), 4.61 (ddd, J=10.1,7.8, 4.5 Hz, 1H), 4.01 (s, 2H), 3.61 (s, 3H), 3.24 (dd, J=14.2, 4.5 Hz,1H), 3.06 (dd, J=14.2, 10.2 Hz, 1H), 1.99-1.85 (m, 1H), 1.85-1.73 (m,1H), 0.86 (t, J=7.3 Hz, 3H).

Example 20

Synthesis of cyclopropyl(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoate(20): The title compound was prepared according to the method presentedfor the synthesis of 1 using intermediate L and intermediate C. MS (m/z)671.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.92 (d, J=7.7Hz, 1H), 8.57 (d, J=4.9 Hz, 1H), 8.49 (d, J=2.3 Hz, 1H), 8.00-7.86 (m,2H), 7.42 (d, J=8.1 Hz, 1H), 6.82-6.60 (m, 2H), 4.85 (d, J=9.7 Hz, 1H),4.71 (ddd, J=10.3, 7.6, 5.2 Hz, 1H), 4.14 (ddd, J=9.3, 4.7, 2.3 Hz, 2H),3.99-3.92 (m, 1H), 3.61 (s, 3H), 3.36 (d, J=12.4 Hz, 1H), 3.23 (dd,J=14.2, 5.3 Hz, 1H), 3.08 (dd, J=14.2, 10.3 Hz, 1H), 2.06 (s, 3H),0.77-0.52 (m, 3H).

Example 21

Synthesis of ethyl(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoate(21): To 15 (600 mg, 0.8 mmol) in DCM (13 mL) was added DIAD (1.15 mL,8.0 mmol), EtOH (0.47 mL, 8.0 mmol) and PPh₃ (1.27 g, 4.83 mmol) and themixture was allowed to stir for 10 min. The reaction mixture wasconcentrated in vacuo and then was purified by column chromatography onsilica gel eluting with EA in hexanes 0-100% to afford 21. MS (m/z)659.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.92 (d, J=7.7Hz, 1H), 8.57 (d, J=4.9 Hz, 1H), 8.50 (d, J=2.3 Hz, 1H), 7.95 (dd,J=8.2, 2.4 Hz, 1H), 7.91 (dd, J=5.0, 0.8 Hz, 1H), 7.47-7.35 (m, 1H),6.77-6.59 (m, 2H), 4.85 (dd, J=8.8, 3.5 Hz, 1H), 4.74 (ddd, J=10.4, 7.8,5.2 Hz, 1H), 4.20-4.08 (m, 3H), 3.95 (dd, J=11.4, 3.6 Hz, 1H), 3.79-3.72(m, 1H), 3.61 (s, 3H), 3.58-3.50 (m, 1H), 3.43 (s, 1H), 3.35 (s, 1H),3.31-3.21 (m, 2H), 3.09 (dd, J=14.2, 10.4 Hz, 1H), 2.07 (s, 3H), 1.20(t, J=7.1 Hz, 3H).

Example 22

Synthesis of methyl(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(5-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-2-yl)propanoate(22): The title compound was prepared according to the method presentedfor the synthesis of 1 using intermediate M and intermediate C. MS (m/z)645.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.86 (d, J=7.7Hz, 1H), 8.58 (d, J=5.0 Hz, 1H), 8.48 (d, J=2.5 Hz, 1H), 7.92 (d, J=4.9Hz, 1H), 7.74 (dd, J=8.2, 2.5 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 6.77-6.61(m, 2H), 4.97 (ddd, J=9.8, 7.7, 5.2 Hz, 1H), 4.85 (dd, J=8.9, 3.6 Hz,1H), 4.15 (d, J=12.6 Hz, 1H), 3.95 (dd, J=11.5, 3.6 Hz, 1H), 3.74 (d,J=12.7 Hz, 1H), 3.67 (s, 3H), 3.62 (s, 3H), 3.59-3.47 (m, 1H), 3.41-3.29(m, 2H), 3.23 (dd, J=14.3, 9.8 Hz, 2H), 2.06 (s, 3H).

Example 23

Synthesis of(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(5-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-2-yl)propanoicacid (23): The title compound was prepared according to the methodpresented for the synthesis of Example 9 starting with 22. MS (m/z)631.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.71 (d, J=8.0Hz, 1H), 8.58 (d, J=4.9 Hz, 1H), 8.48 (d, J=2.5 Hz, 1H), 7.92 (d, J=4.9Hz, 1H), 7.74 (dd, J=8.2, 2.5 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 6.74-6.61(m, 2H), 4.98-4.78 (m, 2H), 4.14 (d, J=12.6 Hz, 1H), 3.95 (dd, J=11.6,3.6 Hz, 1H), 3.73 (d, J=12.8 Hz, 1H), 3.62 (s, 3H), 3.60-3.49 (m, 1H),3.42-3.29 (m, 2H), 3.31-3.09 (m, 2H), 2.05 (s, 3H).

Example 24

Synthesis of methyl(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(4-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)phenyl)propanoate(24): The title compound was prepared according to the method presentedfor the synthesis of 1 using intermediate N and intermediate C. MS (m/z)644.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.89 (d, J=7.7Hz, 1H), 8.55 (d, J=5.0 Hz, 1H), 7.90 (d, J=5.0 Hz, 1H), 7.39 (d, J=8.1Hz, 2H), 7.23 (d, J=8.2 Hz, 2H), 6.70 (dd, J=12.9, 2.3 Hz, 1H), 6.67 (d,J=2.3 Hz, 1H), 4.84 (dt, J=9.8, 5.1 Hz, 1H), 4.70 (ddd, J=10.4, 7.7, 4.8Hz, 1H), 4.15 (d, J=12.6 Hz, 1H), 3.95 (dd, J=11.5, 3.7 Hz, 1H), 3.74(dd, J=12.1, 3.4 Hz, 1H), 3.67 (s, 3H), 3.60 (s, 3H), 3.59-3.50 (m, 1H),3.36 (d, J=11.8 Hz, 1H), 3.27 (d, J=12.2 Hz, 1H), 3.19 (dd, J=14.2, 5.0Hz, 1H), 3.05 (dd, J=14.1, 10.4 Hz, 1H), 2.07 (s, 3H).

Example 25

Synthesis of(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(4-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)phenyl)propanoicacid (25): The title compound was prepared according to the methodpresented for the synthesis of Example 9 starting with 24. MS (m/z)630.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.74 (d, J=8.0Hz, 1H), 8.55 (d, J=5.0 Hz, 1H), 7.90 (d, J=5.0 Hz, 1H), 7.40 (d, J=8.3Hz, 2H), 7.22 (d, J=8.3 Hz, 2H), 6.69 (dd, J=13.0, 2.2 Hz, 1H), 6.65 (d,J=2.3 Hz, 1H), 4.90-4.78 (m, 1H), 4.65 (tt, J=8.0, 4.3 Hz, 1H), 4.15 (d,J=12.5 Hz, 1H), 3.95 (dd, J=11.5, 3.6 Hz, 1H), 3.73 (d, J=12.6 Hz, 1H),3.60 (s, 3H), 3.55 (td, J=11.8, 11.3, 3.0 Hz, 1H), 3.36 (d, J=11.5 Hz,1H), 3.27 (d, J=12.4 Hz, 1H), 3.21 (dd, J=14.1, 4.2 Hz, 1H), 3.01 (dd,J=14.2, 10.7 Hz, 1H), 2.05 (s, 3H).

Example 26

Synthesis of methyl(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(3-methoxy-4-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)phenyl)propanoate(26): The title compound was prepared according to the method presentedfor the synthesis of 1 using intermediate O and intermediate C. MS (m/z)674.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.91 (d, J=7.7Hz, 1H), 8.56 (d, J=4.9 Hz, 1H), 7.94-7.84 (m, 1H), 7.21-7.09 (m, 2H),6.96 (dd, J=8.0, 1.7 Hz, 1H), 6.77-6.63 (m, 2H), 4.84 (td, J=8.8, 3.5Hz, 1H), 4.72 (ddd, J=10.6, 7.7, 4.7 Hz, 1H), 4.15 (d, J=12.6 Hz, 1H),3.95 (dd, J=11.4, 3.6 Hz, 1H), 3.84-3.72 (m, 1H), 3.69 (d, J=3.9 Hz,6H), 3.64-3.58 (m, 4H), 3.31-3.00 (m, 6H), 2.09 (s, 3H).

Example 27

Synthesis of(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(3-methoxy-4-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)phenyl)propanoicacid (27): The title compound was prepared according to the methodpresented for the synthesis of Example 9 starting with 26. MS (m/z)660.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.76 (d, J=8.0Hz, 1H), 8.56 (d, J=5.0 Hz, 1H), 7.89 (dd, J=5.0, 1.4 Hz, 1H), 7.20-7.12(m, 2H), 6.97 (dd, J=8.0, 1.6 Hz, 1H), 6.74-6.61 (m, 2H), 4.84 (dd,J=8.9, 3.5 Hz, 1H), 4.67 (ddd, J=11.6, 7.9, 4.1 Hz, 1H), 4.15 (d, J=12.6Hz, 1H), 3.95 (dd, J=11.5, 3.7 Hz, 1H), 3.71 (s, 5H), 3.69 (s, 3H),3.40-3.31 (m, 1H), 3.31-3.17 (m, 2H), 3.01 (dd, J=14.2, 10.8 Hz, 1H),2.08 (s, 3H).

Example 54

Synthesis of ethyl(S)-2-(2-chloro-6-fluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoate(54): The title compound was prepared according to the method presentedfor the synthesis of 8 using the ethyl ester of intermediate K andintermediate P. MS (m/z) 679.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.16(d, J=7.9 Hz, 1H), 9.00 (s, 1H), 8.57 (d, J=5.0 Hz, 1H), 8.50 (d, J=2.3Hz, 1H), 7.94 (dd, J=8.1, 2.4 Hz, 1H), 7.90 (d, J=5.0 Hz, 1H), 7.41 (d,J=8.1 Hz, 1H), 6.98-6.88 (m, 2H), 4.93 (dd, J=8.9, 3.5 Hz, 1H), 4.74(ddd, J=10.3, 7.9, 5.1 Hz, 1H), 4.20-4.08 (m, 3H), 3.95 (dd, J=11.6, 3.7Hz, 1H), 3.74 (d, J=12.7 Hz, 1H), 3.61 (s, 3H), 3.54 (t, J=9.14 Hz, 1H),3.41 (d, J=12.5 Hz, 1H), 3.25 (m, 2H), 3.09 (dd, J=14.2, 10.2 Hz, 1H),1.20 (t, J=7.1 Hz, 3H).

Example 55

Synthesis of(S)-2-(2-chloro-6-fluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoicacid (55): The title compound was prepared according to the methodpresented for the synthesis of Example 9 starting with 54. MS (m/z)651.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 13.32-12.45 (s, 1H), 9.04 (d,J=8.2 Hz, 1H), 9.00 (s, 1H), 8.57 (d, J=5.0 Hz, 1H), 8.50 (d, J=2.3 Hz,1H), 7.94 (dd, J=8.1, 2.4 Hz, 1H), 7.90 (d, J=5.0 Hz, 1H), 7.41 (d,J=8.1 Hz, 1H), 6.96-6.87 (m, 2H), 5.00-4.84 (m, 1H), 4.76-4.63 (m, 1H),4.15 (d, J=12.7 Hz, 1H), 3.95 (dd, J=11.5, 3.7 Hz, 1H), 3.74 (d, J=12.7Hz, 1H), 3.61 (s, 3H), 3.60-3.49 (m, 1H), 3.40 (d, J=12.7 Hz, 1H), 3.27(m, 2H), 3.04 (dd, J=14.3, 10.6 Hz, 1H).

Example 56

Synthesis of methyl(S)-2-(4-((S)-3-(2,2-difluoroethyl)morpholino)-2-fluoro-6-methylbenzamido)-3-(4-(1-methyl-2,4-dioxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-d]pyrimidin-3(4H)-yl)phenyl)propanoate(56): The title compound was prepared according to the method presentedfor the synthesis of 8 using the ethyl ester of intermediate R andintermediate Q. MS (m/z) 645.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.83(d, J=7.7 Hz, 1H), 7.40-7.29 (m, 2H), 7.14-7.05 (m, 2H), 6.61-6.48 (m,2H), 6.36-5.97 (m, 1H), 4.67 (ddd, J=10.4, 7.7, 4.9 Hz, 1H), 4.28 (d,J=1.8 Hz, 2H), 4.02 (d, J=9.3 Hz, 1H), 3.93-3.80 (m, 4H), 3.66 (s, 3H),3.63 (s, 1H), 3.52 (td, J=11.7, 3.2 Hz, 1H), 3.34 (s, 1H), 3.16 (dd,J=14.1, 4.9 Hz, 1H), 3.09-2.95 (m, 2H), 2.72 (d, J=5.8 Hz, 2H), 2.37 (d,J=14.0 Hz, 1H), 2.05 (s, 3H), 1.77 (q, J=17.5 Hz, 1H).

Example 57

Synthesis of(S)-2-(4-((S)-3-(2,2-difluoroethyl)morpholino)-2-fluoro-6-methylbenzamido)-3-(4-(1-methyl-2,4-dioxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-d]pyrimidin-3(4H)-yl)phenyl)propanoicacid (57): The title compound was prepared according to the methodpresented for the synthesis of Example 9 starting with 56. MS (m/z)631.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.87-12.58 (s, 1H), 8.68 (d,J=8.1 Hz, 1H), 7.36 (d, J=8.2 Hz, 2H), 7.10 (d, J=8.2 Hz, 2H), 6.53 (d,J=8.7 Hz, 2H), 6.34-5.94 (m, 1H), 4.70-4.54 (m, 1H), 4.28 (s, 2H), 4.01(s, 1H), 3.94-3.79 (m, 4H), 3.64 (d, J=11.2 Hz, 1H), 3.52 (d, J=3.3 Hz,1H), 3.33 (s, 1H), 3.31 (s, 3H), 3.22-3.14 (m, 1H), 3.09-2.93 (m, 2H),2.71 (s, 2H), 2.43-2.34 (m, 1H), 2.04 (s, 3H), 1.79 (s, 1H).

Example 58

Synthesis of methyl(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(4-(1-methyl-2,4-dioxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-d]pyrimidin-3(4H)-yl)phenyl)propanoate(58): The title compound was prepared according to the method presentedfor the synthesis of 8 using the ethyl ester of intermediate R andintermediate C. MS (m/z) 649.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.87(d, J=7.7 Hz, 1H), 7.35 (d, J=8.3 Hz, 2H), 7.14-7.07 (m, 2H), 6.69 (d,J=13.5 Hz, 1H), 6.66 (d, J=2.3 Hz, 1H), 4.84 (d, J=9.0 Hz, 1H), 4.68(ddd, J=12.4, 7.8, 4.9 Hz, 1H), 4.29 (s, 2H), 4.15 (d, J=12.6 Hz, 1H),4.00-3.92 (m, 1H), 3.88 (t, J=5.6 Hz, 2H), 3.73 (d, J=12.6 Hz, 1H), 3.66(s, 3H), 3.54 (t, J=10.2 Hz, 1H), 3.35 (d, J=13.3 Hz, 2H), 3.31 (s, 2H),3.16 (dd, J=14.2, 5.0 Hz, 1H), 3.02 (dd, J=14.1, 10.2 Hz, 1H), 2.71 (m,2H), 2.05 (s, 3H).

Example 59

Synthesis of(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(4-(1-methyl-2,4-dioxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-d]pyrimidin-3(4H)-yl)phenyl)propanoicacid (59): The title compound was prepared according to the methodpresented for the synthesis of Example 9 starting with 58. MS (m/z)635.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J=8.0 Hz, 1H),7.41-7.30 (m, 2H), 7.13-7.05 (m, 2H), 6.68 (dd, J=12.9, 2.3 Hz, 1H),6.64 (d, J=2.4 Hz, 1H), 4.84 (dd, J=8.9, 3.5 Hz, 1H), 4.63 (ddd, J=12.0,8.0, 4.4 Hz, 1H), 4.28 (d, J=1.8 Hz, 2H), 4.14 (d, J=12.6 Hz, 1H), 3.95(dd, J=11.3, 3.7 Hz, 1H), 3.88 (t, J=5.6 Hz, 2H), 3.73 (d, J=12.7 Hz,1H), 3.62-3.49 (m, 1H), 3.31 (s, 5H), 3.18 (dd, J=14.2, 4.3 Hz, 1H),2.99 (dd, J=14.2, 10.6 Hz, 1H), 2.71 (s, 1H), 2.04 (s, 3H).

Example 60

Synthesis of methyl(S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(4-(1-methyl-2,4-dioxo-1,2,4,5,6,8-hexahydro-3H-pyrano[3,4-d]pyrimidin-3-yl)phenyl)propanoate(60): The title compound was prepared according to the method presentedfor the synthesis of 8 using the ethyl ester of intermediate S andintermediate B. MS (m/z) 653.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.03(d, J=7.5 Hz, 1H), 7.34 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.3 Hz, 2H), 6.79(d, J=11.6 Hz, 2H), 4.91 (dt, J=12.0, 6.0 Hz, 1H), 4.68-4.56 (m, 3H),4.17 (d, J=12.7 Hz, 1H), 3.96 (dd, J=11.4, 3.8 Hz, 1H), 3.84-3.70 (m,3H), 3.64 (s, 3H), 3.61-3.51 (m, 1H), 3.44 (d, J=12.7 Hz, 1H), 3.26 (d,J=13.2 Hz, 1H), 3.21 (s, 3H), 3.17 (d, J=5.3 Hz, 1H), 3.15-3.01 (m, 2H),2.39-2.24 (m, 2H).

Example 61

Synthesis of(S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(4-(1-methyl-2,4-dioxo-1,2,4,5,6,8-hexahydro-3H-pyrano[3,4-d]pyrimidin-3-yl)phenyl)propanoicacid (61): The title compound was prepared according to the methodpresented for the synthesis of Example 9 starting with 60. MS (m/z)639.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J=7.8 Hz, 1H), 7.35(dd, J=8.5, 2.0 Hz, 2H), 7.16-7.00 (m, 2H), 6.78 (d, J=11.6 Hz, 2H),5.04-4.82 (m, 1H), 4.64-4.49 (m, 3H), 4.16 (d, J=12.7 Hz, 1H), 3.96 (dd,J=11.5, 3.7 Hz, 1H), 3.83-3.70 (m, 3H), 3.62-3.49 (m, 1H), 3.43 (d,J=12.7 Hz, 1H), 3.26 (d, J=12.5 Hz, 1H), 3.21 (s, 3H), 3.16 (dd, J=14.2,4.8 Hz, 1H), 3.02 (dd, J=14.2, 9.7 Hz, 1H), 2.33 (qd, J=4.3, 3.0, 2.4Hz, 2H).

Example 62

Synthesis of methyl(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(4-(1-methyl-2,4-dioxo-1,2,4,5,6,8-hexahydro-3H-pyrano[3,4-d]pyrimidin-3-yl)phenyl)propanoate(62): The title compound was prepared according to the method presentedfor the synthesis of 8 using the ethyl ester of intermediate S andintermediate C. MS (m/z) 671.2 [M+Na]. 1H NMR (400 MHz, DMSO-d6) δ 8.87(d, J=7.7 Hz, 1H), 7.35 (d, J=8.2 Hz, 2H), 7.10 (d, J=8.2 Hz, 2H), 6.70(d, J=13.5 Hz, 1H), 6.66 (s, 1H), 4.84 (d, J=7.7 Hz, 1H), 4.76-4.64 (m,1H), 4.60 (s, 2H), 4.15 (d, J=12.6 Hz, 1H), 4.03-3.90 (m, 1H), 3.86-3.70(m, 3H), 3.66 (s, 3H), 3.55 (t, J=10.7 Hz, 1H), 3.21 (s, 4H), 3.03 (dd,J=14.1, 10.3 Hz, 1H), 2.33 (d, J=2.5 Hz, 3H), 2.06 (s, 3H).

Example 63

Synthesis of(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(4-(1-methyl-2,4-dioxo-1,2,4,5,6,8-hexahydro-3H-pyrano[3,4-d]pyrimidin-3-yl)phenyl)propanoicacid (63): The title compound was prepared according to the methodpresented for the synthesis of Example 9 starting with 62. MS (m/z)635.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J=8.0 Hz, 1H),7.41-7.33 (m, 2H), 7.15-7.03 (m, 2H), 6.68 (dd, J=12.9, 2.3 Hz, 1H),6.64 (d, J=2.3 Hz, 1H), 4.84 (dd, J=9.0, 3.6 Hz, 1H), 4.69-4.56 (m, 3H),4.14 (d, J=12.6 Hz, 1H), 3.95 (dd, J=11.4, 3.6 Hz, 1H), 3.79 (t, J=5.5Hz, 2H), 3.76-3.68 (m, 1H), 3.61-3.49 (m, 1H), 3.35 (d, J=12.3 Hz, 1H),3.27 (d, J=12.5 Hz, 1H), 3.21 (s, 4H), 2.99 (dd, J=14.2, 10.6 Hz, 1H),2.40-2.25 (m, 2H), 2.04 (s, 3H).

Example 64

Synthesis of(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(4-(1-methyl-2,4-dioxo-1,2,4,5,6,7-hexahydro-3H-cyclopenta[d]pyrimidin-3-yl)phenyl)propanoicacid (64): The title compound was prepared according to the methodpresented for the synthesis of 1 using the ethyl ester of intermediate Tand intermediate C. MS (m/z) 619.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ8.72 (d, J=8.0 Hz, 1H), 7.35 (dd, J=8.5, 2.0 Hz, 2H), 7.11-7.00 (m, 2H),6.68 (dd, J=12.9, 2.4 Hz, 1H), 6.64 (d, J=2.4 Hz, 1H), 4.84 (dd, J=8.8,3.5 Hz, 1H), 4.63 (ddd, J=10.6, 8.0, 4.2 Hz, 1H), 4.14 (d, J=12.6 Hz,1H), 3.94 (dd, J=11.4, 3.6 Hz, 1H), 3.73 (d, J=12.7 Hz, 1H), 3.54 (td,J=11.7, 3.5 Hz, 1H), 3.35 (d, J=12.2 Hz, 1H), 3.29 (s, 3H), 3.18 (dd,J=14.3, 4.3 Hz, 1H), 3.05-2.89 (m, 3H), 2.61 (t, J=7.4 Hz, 2H), 2.04 (s,3H).

Example 65

Synthesis of ethyl(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(4-(1-methyl-2,4-dioxo-1,2,4,5,6,7-hexahydro-3H-cyclopenta[d]pyrimidin-3-yl)phenyl)propanoate(65): To 64 (30 mg, 0.05 mmol), TPP (38 mg, 0.145 mmol) and EtOH (0.03mL, 0.48 mmol) in DCM was added DIAD (0.05 mL, 0.24 mmol). The mixturewas allowed to stir for 60 min at RT. Upon completion, the mixture wasacidified with TFA, and the volatiles were removed under reducedpressure. The crude material was dissolved in DMSO and chromatographedon C-18 modified silica gel eluting with acetonitrile in water (0.4%TFA) to afford compound 65. MS (m/z) 647.3 [M+H]+. 1H NMR (400 MHz,DMSO-d6) 5 8.86 (d, J=7.6 Hz, 1H), 7.39-7.28 (m, 2H), 7.12-7.01 (m, 2H),6.75-6.67 (m, 1H), 6.66 (d, J=2.3 Hz, 1H), 4.92-4.76 (m, 1H), 4.65 (ddd,J=9.9, 7.6, 5.2 Hz, 1H), 4.19-4.06 (m, 3H), 3.95 (dd, J=11.4, 3.7 Hz,1H), 3.73 (d, J=12.7 Hz, 1H), 3.62-3.43 (m, 1H), 3.36 (d, J=12.4 Hz,1H), 3.29 (s, 4H), 3.15 (dd, J=14.1, 5.3 Hz, 1H), 3.10-3.00 (m, 1H),2.97 (q, J=7.6, 6.6 Hz, 2H), 2.61 (t, J=7.5 Hz, 2H), 2.13-1.92 (m, 5H),1.17 (t, J=7.1 Hz, 3H).

Example 66

Synthesis of(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(4-(1-methyl-2,4-dioxo-1,2,5,7-tetrahydrofuro[3,4-d]pyrimidin-3(4H)-yl)phenyl)propanoicacid (66): The title compound was prepared according to the methodpresented for the synthesis of 1 using the ethyl ester of intermediate Uand intermediate C. MS (m/z) 621.2 [M+H 1H NMR (400 MHz, DMSO-d6) δ 8.72(d, J=8.0 Hz, 1H), 7.42-7.30 (m, 2H), 7.16-7.03 (m, 2H), 6.68 (dd,J=12.9, 2.3 Hz, 1H), 6.64 (d, J=2.3 Hz, 1H), 5.06 (t, J=3.6 Hz, 2H),4.86 (t, J=3.6 Hz, 3H), 4.64 (ddd, J=10.7, 8.0, 4.2 Hz, 1H), 4.14 (d,J=12.6 Hz, 1H), 3.94 (dd, J=11.4, 3.6 Hz, 1H), 3.73 (d, J=12.5 Hz, 1H),3.63-3.47 (m, 1H), 3.35 (d, J=12.2 Hz, 1H), 3.23 (s, 5H), 2.99 (dd,J=14.2, 10.7 Hz, 1H), 2.03 (s, 3H).

Example 67

Synthesis of ethyl(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(6-(1-methyl-2,4-dioxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-d]pyrimidin-3(4H)-yl)pyridin-3-yl)propanoate(67): The title compound was prepared according to the method presentedfor the synthesis of 8 using the ethyl ester of intermediate V andintermediate C. MS (m/z) 664.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.90(d, J=7.7 Hz, 1H), 8.45 (d, J=2.3 Hz, 1H), 7.95 (s, 1H), 7.89 (dd,J=8.2, 2.4 Hz, 1H), 7.30 (dd, J=8.1, 0.7 Hz, 1H), 6.75-6.64 (m, 2H),4.84 (dd, J=8.8, 3.5 Hz, 1H), 4.71 (ddd, J=10.4, 7.8, 5.2 Hz, 1H), 4.29(s, 2H), 4.19-4.06 (m, 3H), 3.99-3.84 (m, 3H), 3.73 (d, J=12.5 Hz, 1H),3.59-3.49 (m, 1H), 3.31 (s, 4H), 3.28-3.16 (m, 2H), 3.07 (dd, J=14.3,10.3 Hz, 1H), 2.89 (s, 2H), 2.77-2.66 (m, 4H), 2.06 (s, 3H), 1.18 (t,J=7.1 Hz, 3H).

Example 68

Synthesis of(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(6-(1-methyl-2,4-dioxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-d]pyrimidin-3(4H)-yl)pyridin-3-yl)propanoicacid (68): The title compound was prepared according to the methodpresented for the synthesis of Example 9 starting with 67. MS (m/z)636.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J=8.1 Hz, 1H), 8.46(d, J=2.3 Hz, 1H), 7.88 (dd, J=8.2, 2.4 Hz, 1H), 7.33-7.26 (m, 1H),6.73-6.62 (m, 2H), 4.84 (dd, J=8.8, 3.6 Hz, 1H), 4.67 (ddd, J=11.9, 8.0,4.2 Hz, 1H), 4.29 (s, 2H), 4.14 (d, J=12.6 Hz, 1H), 3.95 (dd, J=11.4,3.6 Hz, 1H), 3.88 (d, J=11.0 Hz, 1H), 3.73 (d, J=11.8 Hz, 1H), 3.59-3.48(m, 1H), 3.35 (d, J=12.3 Hz, 1H), 3.31 (s, 5H), 3.02 (dd, J=14.3, 10.9Hz, 1H), 2.73 (s, 2H), 2.03 (s, 3H).

Example 69

Synthesis of(S)-2-(4-((S)-3-(2,2-difluoroethyl)morpholino)-2-fluoro-6-methylbenzamido)-3-(6-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridin-3-yl)propanoicacid (69): The title compound was prepared according to the methodpresented for the synthesis of 1 using the ethyl ester of intermediate Kand intermediate Q. MS (m/z) 627.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ9.00 (s, 1H), 8.75 (d, J=8.2 Hz, 1H), 8.57 (d, J=5.0 Hz, 1H), 8.50 (d,J=2.4 Hz, 1H), 7.94 (dd, J=8.3, 2.4 Hz, 1H), 7.92-7.89 (m, 1H), 7.42 (d,J=8.0 Hz, 1H), 6.53 (t, J=6.1 Hz, 2H), 6.36-5.96 (m, 1H), 4.75-4.61 (m,1H), 4.03 (m, 1H), 3.90 (d, J=9.1 Hz, 1H), 3.84 (d, J=11.8 Hz, 1H), 3.61(s, 3H), 3.58-3.46 (m, 1H), 3.35-3.13 (m, 2H), 3.04 (dd, J=14.4, 10.9Hz, 2H), 2.03 (s, 3H).

Example 70

Synthesis of(S)-2-(4-((S)-3-(2,2-difluoroethyl)morpholino)-2-fluoro-6-methylbenzamido)-3-(4-(1-methyl-2,4-dioxo-1,2,5,7-tetrahydrofuro[3,4-d]pyrimidin-3(4H)-yl)phenyl)propanoicacid (70): The title compound was prepared according to the methodpresented for the synthesis of 1 using the ethyl ester of intermediate Wand intermediate Q. MS (m/z) 617.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ8.68 (d, J=8.0 Hz, 1H), 7.42-7.30 (m, 2H), 7.16-7.04 (m, 2H), 6.61-6.44(m, 2H), 6.16 (tt, J=56.3, 4.5 Hz, 1H), 5.06 (t, J=3.6 Hz, 2H), 4.86 (t,J=3.6 Hz, 2H), 4.64 (ddd, J=11.9, 8.1, 4.2 Hz, 1H), 4.01 (d, J=9.3 Hz,1H), 3.89 (dd, J=11.2, 3.5 Hz, 1H), 3.84 (d, J=11.6 Hz, 1H), 3.69-3.58(m, 1H), 3.52 (td, J=11.6, 3.1 Hz, 1H), 3.31 (d, J=12.6 Hz, 1H), 3.23(s, 3H), 3.19 (dd, J=14.3, 4.3 Hz, 1H), 3.08-2.85 (m, 2H), 2.43-2.25 (m,1H), 2.03 (s, 3H), 1.75 (dd, J=19.1, 14.8 Hz, 1H).

α4β7 Integrin Cell Capture Assay

The potency of inhibitors in preventing α4β7 integrin interaction withMadCAM-1 was measured by monitoring the capture of α4β7 integrinexpressing cells on a recombinant MadCAM-1 extracellular domain-coatedplate.

384-well plates (Corning 3702) were coated with MadCAM-1 extracellulardomain by dispensing 20 μL of MAdCAM-1 at 1.0 μg/mL per well andincubating overnight at 4° C. The plates were then washed with PBS andblocked with 3% BSA for 2 hours before being washed again.

RPM18866 cells were spun down and re-suspended in assay medium(DMEM+0.5% FBS+0.5 mM MnCl₂) at a density of 0.5×10⁶ cells/mL. The cellswere then dispensed (60 μL/well) to a 384-well plate (Greiner 781280)that was previously spotted with 60 nL of test compound per well. Theplates were incubated at 37° C. for 1 hour. 50 μL of cells weretransferred to the blocked, MadCAM-1-coated plates and incubated for 30minutes at 37° C. 10 μL of 12% glutaraldehyde containing Hoechst 33342(0.06 mg/mL) was added to the cells (2% glutaraldehyde and 0.01 mg/mLfinal concentrations). The plates were incubated for 90 minutes at roomtemperature. The plates were then washed 3 times with 70 μL of PBS perwell and imaged on a Cellomics ArrayScan instrument. The cells that werebound to the plate were counted and plotted against the compoundconcentration to determine the EC₅₀ of the test compounds. Results arepresented in Tables 1 and 2.

α4β1 Cell Capture Assay

The potency of inhibitors in preventing α4β1 integrin interaction withVCAM-1 was measured by monitoring the capture of α4β1 expressing cellsto a recombinant VCAM-1 extracellular domain-coated plate.

384-well plates (Corning 3702) were coated with VCAM-1 extracellulardomain by dispensing 20 μL of VCAM-1 at 0.5 μg/ml per well andincubating overnight at 4° C. The plates were then washed with PBS andblocked with 3% BSA for 2 hours before being washed again.

Jurkat cells were spun down and re-suspended in assay medium (DMEM+0.5%FBS+0.5 mM MnCl₂) at a density of 0.5×10⁶ cells/ml. The cells were thendispensed (60 μL/well) to a 384-well plate (Greiner 781280) that waspreviously spotted with 60 nL of test compound per well. The plates wereincubated at 37° C. for 1 hour. 50 μL of cells were transferred to theblocked, VCAM-1-coated plates and incubated for 30 minutes at 37° C. 10μl of 12% glutaraldehyde containing Hoechst 33342 (0.06 mg/mL) was addedto the cells (2% glutaraldehyde and 0.01 mg/ml Hoechst 33342 finalconcentrations). The plates were incubated for 90 minutes at roomtemperature. The plates were then washed 3 times with 70 μL of PBS perwell and imaged on a Cellomics ArrayScan instrument. The cells that werebound to the plate were counted and plotted against the compoundconcentration to determine the EC₅₀ of the test compounds. Results arepresented in Tables 1 and 2.

TABLE 1 α4β7 α4β1 Example EC50 EC50 # (nM) (nM) 1 1.4 10.3 2 13.6 905 30.5 18.5 4 1.2 63.7 5 0.2 16.6 6 0.3 9.9 7 0.5 15.3 9 1.6 117 11 0.530.1 13 0.8 38.9 15 0.21 10.6 17 0.7 58.9 19 2.0 127 23 0.2 9.8 25 0.13.4 27 0.1 8.6 55 0.1 3.4 57 0.2 2.8 59 0.1 2.9 61 0.4 11.5 63 0.1 3.764 0.1 1.8 66 0.1 4.8 68 0.3 14.9 69 0.2 20.8 70 3.9 2.4

TABLE 2 α4β7 α4β1 Ex M/Z EC50 EC50 # Structure 1H-NMR [M + H]+ (nM) (nM)28

¹H NMR (400 MHz, DMSO-d₆) δ 12.69 (s, 1H), 8.66 (s, 1H), 7.62-7.55 (m,2H), 7.52 (d, J = 10.2 Hz, 1H), 7.46-7.34 (m, 3H), 7.25-7.17 (m, 2H),7.14-7.05 (m, 2H), 6.68 (s, 2H), 6.57 (d, J = 11.3 Hz, 2H), 5.70 (p, J =8.4 Hz, 1H), 4.47 (s, 3H), 3.64 (s, 6H), 3.53 (q, J = 7.0 Hz, 2H), 3.09(dd, J = 14.0, 4.7 Hz, 1H), 2.93 (dd, J = 14.1, 9.5 Hz, 1H), 1.19 (t, J= 7.0 Hz, 3H). 673.5 7.2 70.7 29

1H MR (400 MHz, DMSO-d₆) δ 8.85 (dd, J = 7.8, 2.9 Hz, 1H), 7.16 (d, J =9.3 Hz, 1H), 7.12-7.05 (m, 1H), 6.86 (d, J = 7.7 Hz, 1H), 6.77 (d, J =12.0 Hz, 2H), 6.51 (s, 1H), 4.92 (d, J = 11.6 Hz, 1H), 4.58-4.49 (m,1H), 4.16 (d, J = 12.6 Hz, 1H), 3.95 (dd, J = 11.3, 3.4 Hz, 1H), 3.74(d, J = 14.3 Hz, 1H), 3.56 (m, 1H), 3.50 (s, 3H), 3.43 (d, J = 12.8 Hz,1H), 3.24 (t, J = 14.8 Hz, 1H), 3.10 (dd, J = 662.2 0.6 29.0 14.3, 4.6Hz, 1H), 3.04-2.90 (m, 1H), 2.49 (s, 3H), 1.97 (s, 3H). 30

1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 7.8 Hz, 1H), 7.20 (s, 4H), 6.78(d, J = 11.7 Hz, 2H), 6.31 (s, 1H), 4.91 (tt, J = 8.7, 5.4 Hz, 1H), 4.52(ddd, J = 9.2, 7.8, 4.9 Hz, 1H), 4.17 (d, J = 12.7 Hz, 1H), 3.96 (dd, J= 11.5, 3.8 Hz, 1H), 3.73 (m, 1H), 3.72 (s, 3H), 3.56 (td, J = 11.9, 3.4Hz, 1H), 3.47-3.43 (m, 1H), 3.41 (s, 3H), 3.25 (t, J = 12.3 Hz, 1H),3.09 (dd, J = 14.0, 4.9 Hz, 1H), 3.01- 2.88 (m, 1H), 2.41 (s, 3H). 610.30.5 10.1 31

1H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 8.1 Hz, 1H), 7.19 (d, J = 11.5Hz, 1H), 7.12 (t, J = 8.7 Hz, 1H), 6.92 (m, 1H), 6.68 (d, J = 13.9 Hz,1H), 6.64 (s, 1H), 4.89-4.78 (m, 1H), 4.61 (m, 1H), 4.14 (d, J = 12.7Hz, 1H), 3.94 (d, J = 11.7 Hz, 1H), 3.73 (d, J = 14.6 Hz, 1H), 3.52 (m,1H), 3.41 (s, 3H), 3.35 (d, J = 15.3 Hz, 1H), 3.26 (d, J = 13.2 Hz, 1H),3.21 (s, 3H), 3.13 (dd, J = 13.8, 3.7 Hz, 1H), 2.95- 621.2 0.2 11.6 2.86(m, 1H), 2.02 (s, 6H), 1.97 (s, 3H). 32

1H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.1Hz, 2H), 7.08 (d, J = 8.1 Hz, 2H), 6.76 (d, J = 10.0 Hz, 1H), 6.44 (d, J= 11.3 Hz, 2H), 4.58- 4.52 (m, 1H), 4.34- 4.28 (m, 1H), 3.41 (s, 2H),3.21 (s, 3H), 3.13 (dd, J = 13.9, 4.6 Hz, 1H), 2.95 (dd, J = 14.0, 10.0Hz, 1H), 2.10 (s, 3H), 1.82-1.72 (m, 1H), 1.59-1.47 (m, 1H), 0.93 (t, J= 7.3 Hz, 3H). 583.2 1.2 14.4 33

1H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J = 7.8 Hz, 1H), 7.37 (dd, J =14.4, 8.7 Hz, 4H), 7.26 (d, J = 2.9 Hz, 1H), 7.16 (d, J = 8.3 Hz, 2H),6.76 (d, J = 9.5 Hz, 1H), 6.45 (d, J = 11.6 Hz, 2H), 4.58- 4.47 (m, 1H),4.30 (d, J = 10.1 Hz, 1H), 3.48 (s, 3H), 3.14 (dd, J = 14.2, 4.6 Hz,1H), 3.00 (dd, J = 14.2, 9.8 Hz, 1H), 2.93 (s, 6H), 1.76 (ddd, J = 13.5,7.3, 3.2 Hz, 1H), 1.52 (ddd, J = 13.6, 10.4, 7.1 Hz, 1H), 0.92 (t, J =7.3 Hz, 3H). 648.3 2.5 104.9 34

1H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J = 8.0 Hz, 1H), 7.68 (dd, J =10.1, 2.8 Hz, 1H), 7.60 (dd, J = 9.4, 4.9 Hz, 1H), 7.58- 7.49 (m, 1H),7.33 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 8.1 Hz, 2H), 6.77 (d, J = 9.5 Hz,1H), 6.46 (d, J = 11.4 Hz, 2H), 4.63- 4.53 (m, 1H), 4.38- 4.25 (m, 1H),3.66 (s, 3H), 3.17 (d, J = 13.8, 4.6 Hz, 1H), 2.99 (dd, J = 13.9, 10.1Hz, 1H), 2.23 (s, 3H), 1.85-1.70 (m, 1H), 1.61-1.45 (m, 620.2 3.2 61.41H), 0.93 (t, J = 7.3 Hz, 3H). 35

1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.85 (d, J = 7.9 Hz, 1H), 8.71(s, 1H), 8.27 (s, 1H), 7.74 (d, J = 6.0 Hz, 1H), 7.67 (d, J = 8.0 Hz,2H), 7.39 (d, J = 8.0 Hz, 2H), 6.77 (d, J = 11.6 Hz, 2H), 4.96-4.86 (m,1H), 4.63-4.55 (m, 1H), 4.17 (d, J = 12.7 Hz, 1H), 3.96 (dd, J = 11.4,3.2 Hz, 1H), 3.74 (d, J = 14.0 Hz, 1H), 3.71 (s, 3H), 3.62-3.50 (m, 1H),3.43 (d, J = 12.7 Hz, 1H), 3.26 (d, J = 16.6 Hz, 1H), 3.18 (dd, J =617.2 1.1 34.1 13.8, 4.7 Hz, 1H), 3.02 (dd, J = 13.6, 10.0 Hz, 1H). 36

1H NMR (400 MHz, DMSO-d6) δ 8.90 (d, J = 7.8 Hz, 1H), 7.42- 7.29 (m,4H), 7.26 (d, J = 2.8 Hz, 1H), 71.6 (d, J = 8.2 Hz, 2H), 6.77 (d, J =11.6 Hz, 2H), 4.91 (dd, J = 8.6, 3.6 Hz, 1H), 4.61- 4.50 (m, 1H), 4.15(d, J = 12.7 Hz, 1H), 3.94 (dd, J = 11.5, 3.8 Hz, 1H), 3.73 (d, J = 12.6Hz, 1H), 3.60-3.49 (m, 1H), 3.49-3.45 (m, 3H), 3.42 (d, J = 12.5 Hz,1H), 3.24 (d, J = 10.9 Hz, 1H), 3.16 (dd, J = 14.3, 4.7 Hz, 1H), 676.31.2 27.3 3.02 (dd, J = 14.2, 9.8 Hz, 1H), 2.93 (s, 6H). 37

1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 8.1 Hz, 1H), 7.29 (d, J = 7.9Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H), 6.76 (d, J = 11.7 Hz, 2H), 4.96-4.87(m, 1H), 4.61-4.54 (m, 1H), 4.16 (d, J = 13.0 Hz, 1H), 3.98- 3.93 (m,1H), 3.73 (d, J = 16.2 Hz, 1H), 3.61-3.54 (m, 3H), 3.41 (s, 3H), 3.26-3.22 (m, 1H), 3.21 (s, 3H), 3.17-3.12 (m, 1H), 2.99-2.91 (m, 1H), 2.10(s, 3H). 611.2 0.4 9.8 38

1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 7.9 Hz, 1H), 8.24 (d, J = 8.4Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 11.7 Hz, 2H), 4.90 (qd,J = 8.6, 3.3 Hz, 1H), 4.56 (ddd, J = 9.7, 8.0, 4.7 Hz, 1H), 4.16 (d, J =12.7 Hz, 1H), 3.95 (dd, J = 11.5, 3.8 Hz, 1H), 3.74 (d, J = 12.9 Hz,1H), 3.58 (m, 1H), 3.54 (s, 3H), 3.43 (d, J = 13.4 Hz, 1H), 3.29-3.18(m, 1H), 3.15 (dd, J = 13.9, 4.7 Hz, 1H), 2.98 (dd, J = 13.9, 595.2 4.986.1 9.8 Hz, 1H), 2.37 (s, 3H), 2.35 (s, 3H). 39

1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J = 7.7 Hz, 1H), 7.17 (d, J = 8.8Hz, 1H), 7.10 (t, J = 7.3 Hz, 1H), 6.92 (t, J = 6.1 Hz, 1H), 6.76 (d, J= 11.5 Hz, 2H), 4.96- 4.86 (m, 1H), 4.60- 4.50 (m, 1H), 4.16 (d, J =12.8 Hz, 1H), 3.96 (d, J =10.9 Hz, 1H), 3.74 (d, J = 12.6 Hz, 1H), 3.56(t, J = 11.8 Hz, 1H), 3.46- 3.42 (m, 1H), 3.40 (s, J = 2.2 Hz, 3H), 3.25(d, J = 13.0 Hz, 1H), 3.21 (s, J = 2.1 Hz, 3H), 3.14-3.07 (m, 625.2 0.412.8 1H), 2.98-2.89 (m, 1H), 2.03 (s, J = 2.6 Hz, 3H), 1.97 (s, 3H). 40

1H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 8.3 Hz, 1H), 7.21 (d, J = 11.7Hz, 1H), 7.14 (t, J = 8.8 Hz, 1H), 6.93 (t, J = 7.0 Hz, 1H), 6.67 (d, J= 18.0 Hz, 1H), 6.64 (s, 1H), 4.93-4.74 (m, 1H), 4.68-4.56 (m, 1H), 4.14(d, J = 11.0 Hz, 1H), 3.94 (d, J = 11.0 Hz, 1H), 3.73 (d, J = 11.0 Hz,1H), 3.58-3.49 (m, 1H), 3.47 (s, 3H), 3.35 (d, J = 12.9 Hz, 1H), 3.27(d, J = 16.7 Hz, 1H), 3.16-3.11 (m, 1H), 2.96-2.87 (m, 605.2 0.3 7.71H), 2.57 (s, 3H), 2.03 (d, J = 2.0 Hz, 3H), 2.01 (d, J = 4.0 Hz, 3H),1.92 (s, 3H). 41

1H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J = 7.9 Hz, 1H), 7.10 (s, 1H), 7.03(d, J = 8.0 Hz, 1H), 6.90- 6.84 (m, 1H), 6.69 (d, J = 13.1 Hz, 1H), 6.66(s, 1H), 6.30 (s, 1H), 4.88-4.78 (m, 1H), 4.62-4.54 (m, 1H), 4.15 (d, J=12.5 Hz, 1H), 3.95 (d, J = 14.1 Hz, 1H), 3.73 (d, J = 16.1 Hz, 1H),3.68 (s, 3H), 3.55 (t, J = 12.8 Hz, 1H), 3.41 (s, 3H), 3.35 (d, J = 11.5Hz, 1H), 3.27 (d, J = 10.9 Hz, 1H), 3.09 (dd, J = 14.1, 4.0 Hz, 1H),620.2 0.3 8.3 2.91 (dd, J = 13.9, 10.6 Hz, 1H), 2.42 (s, 3H), 2.08 (s,3H), 1.98 (d, J = 2.2 Hz, 3H). 42

1H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 7.7Hz, 1H), 7.15-7.10 (m, 2H), 6.73-6.64 (m, 2H), 4.89-4.78 (m, 1H),4.59-4.53 (m, 1H), 4.14 (d, J = 12.7 Hz, 1H), 3.94 (d, J = 11.9 Hz, 1H),3.73 (d, J = 10.5 Hz, 1H), 3.56 (d, J = 12.8 Hz, 1H), 3.51 (s, 3H), 3.35(d, J = 11.5 Hz, 1H), 3.27 (d, J = 12.1 Hz, 1H), 3.11 (dd, J = 14.1, 4.4Hz, 1H), 2.95 (dd, J = 13.6, 10.4 Hz, 1H), 2.36 (s, 3H), 2.30 (s, 3H),605.2 0.3 5.8 2.15 (s, 3H), 2.10 (s, 3H). 43

1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 7.8 Hz, 1H), 8.44 (d, J = 2.3Hz, 1H), 7.84 (dd, J = 8.2, 2.4 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 6.78(d, J = 9.4 Hz, 1H), 6.46 (d, J = 11.6 Hz, 2H), 5.73 (s, 1H), 4.62- 4.42(m, 1H), 4.31 (d, J = 8.9 Hz, 1H), 3.32 (s, 3H), 3.26-2.93 (m, 2H), 2.32(s, 3H), 1.78 (ddd, J = 13.9, 7.3, 3.2 Hz, 1H), 1.54 (dd, J = 6.9, 3.4Hz, 1H), 0.92 (d, J = 7.4 Hz, 2H). 570.2 15.9 661.3 44

1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 8.5 Hz, 1H), 8.73 (s, 1H),8.19-8.11 (m, 1H), 7.79 (dd, J = 10.0, 2.6 Hz, 1H), 7.71-7.61 (m, 3H),6.79 (d, J = 9.5 Hz, 1H), 6.45 (d, J = 11.5 Hz, 2H), 4.77-4.69 (m, 1H),4.37-4.26 (m, 1H), 3.69 (s, 3H), 3.38-3.30 (m, 1H), 3.08 (dd, J = 14.2,10.8 Hz, 1H), 2.24 (s, 3H), 1.83-1.72 (m, 1H), 1.59-1.47 (m, 1H), 0.93(t, J = 7.4 Hz, 3H). 621.2 2.9 37.6 45

1H NMR (400 MHz, DMSO-d6) δ 8.92 (d, J = 7.6 Hz, 1H), 8.44 (d, J = 2.3Hz, 1H), 7.85 (dd, J = 8.1, 2.4 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 6.80(d, J = 9.4 Hz, 1H), 6.47 (d, J = 11.6 Hz, 2H), 5.73 (s, 1H), 4.64 (ddd,J = 9.8, 7.5, 5.1 Hz, 1H), 4.32 (d, J = 8.7 Hz, 1H), 3.65 (s, 3H), 3.32(s, 3H), 3.27-2.97 (m, 2H), 2.32 (s, 3H), 1.78 (ddd, J = 13.9, 7.4, 3.3Hz, 1H), 1.53 (ddd, J = 13.8, 10.4, 7.1 Hz, 1H), 0.93 (t, J = 584.2 NANA 7.3 Hz, 3H). 46

1H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 1H), 9.05-8.93 (m, 2H), 8.58 (d, J= 4.9 Hz, 1H), 8.51 (d, J = 2.3 Hz, 1H), 7.96 (dd, J = 8.2, 2.4 Hz, 1H),7.90 (dd, J = 5.0, 0.7 Hz, 1H), 7.51-7.41 (m, 1H), 6.79-6.64 (m, 2H),4.83 (ddd, J = 10.1, 7.6, 5.5 Hz, 1H), 4.50-4.30 (m, 2H), 4.16 (d, J =12.6 Hz, 1H), 4.01-3.90 (m, 1H), 3.76 (d, 2H), 3.61 (s, 3H), 3.59- 3.50(m, 1H), 3.45- 3.32 (m, 3H), 3.32- 3.05 (m, 7H), 2.08 (s, 3H), 1.22 (td,J = 7.2, 2.1 Hz, 7H) 730.3 NA NA 47

1H NMR (400 MHz, DMSO-d6) δ 9.13 (d, J = 7.6 Hz, 1H), 9.00 (s, 1H), 8.57(d, J = 5.0 Hz, 1H), 8.51 (d, J = 2.2 Hz, 1H), 7.98- 7.86 (m, 2H), 7.42(d, J = 8.1 Hz, 1H), 6.79 (d, J = 11.7 Hz, 2H), 5.83-5.74 (m, 2H),4.99-4.87 (m, 1H), 4.77-4.67 (m, 1H), 4.16 (d, J = 12.7 Hz, 1H), 3.96(dd, J = 11.4, 3.7 Hz, 1H), 3.74 (d, J = 12.8 Hz, 1H), 3.61 (s, 3H),3.54 (d, J = 10.6 Hz, 1H), 3.44 (d, J = 12.6 Hz, 1H), 3.24 (dd, J =14.3, 5.4 Hz, 2H), 3.12 (dd, J = 14.3, 749.7 NA NA 10.3 Hz, 1H), 1.16(s, 9H). 48

1H NMR (400 MHz, DMSO-d6) δ 9.34 (dd, J = 6.9, 3.3 Hz, 1H), 9.01 (s,1H), 8.58 (d, J = 4.9 Hz, 2H), 8.03 (dd, J = 8.4, 2.2 Hz, 1H), 7.92 (d,J = 4.9 Hz, 1H), 7.50-7.41 (m, 3H), 7.28 (t, J = 7.4 Hz, 1H), 7.04 (d, J= 7.9 Hz, 2H), 6.82 (d, J = 11.7 Hz, 2H), 4.93 (s, 1H), 4.92-4.84 (m,1H), 4.17 (d, J = 12.7 Hz, 1H), 3.96 (dd, J = 11.4, 3.7 Hz, 1H), 3.75(d, J = 13.0 Hz, 1H), 3.62 (s, 3H), 3.60-3.53 (m, 1H), 3.45 (d, J = 12.2Hz, 710.9 NA NA 1H), 3.37 (d, J = 7.9 Hz, 1H), 3.34-3.30 (m, 1H),3.29-3.21 (m, 1H). 49

1H NMR (400 MHz, DMSO-d6) δ 9.17 (d, J = 7.3 Hz, 1H), 9.01 (s, 1H), 8.58(d, J = 5.0 Hz, 1H), 8.51 (d, J = 2.2 Hz, 1H), 7.94 (d, J = 8.5 Hz, 1H),7.90 (d, J = 5.0 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 6.81 (d, J = 11.8Hz, 2H), 4.93 (d, J = 10.2 Hz, 1H), 4.75 (q, J = 7.4 Hz, 1H), 4.47-4.27(m, 2H), 4.18 (d, J = 12.8 Hz, 1H), 4.01-3.92 (m, 1H), 3.75 (d, J = 12.8Hz, 1H), 3.61 (s, 3H), 3.55 (t, J = 11.9 Hz, 1H), 3.45 (d, J = 734.4 NANA 12.7 Hz, 1H), 3.37 (s, 2H), 3.26 (dd, J = 14.2, 5.7 Hz, 1H), 3.20 (s,1H), 3.18 (m, 5H), 1.20 (td, J = 7.2, 2.2 Hz, 6H). 50

1H NMR (400 MHz, DMSO-d6) δ 9.18 (d, J = 7.1 Hz, 1H), 9.01 (s, 1H), 8.58(d, J = 5.0 Hz, 2H), 8.04 (dd, J = 8.1, 2.3 Hz, 1H), 7.92 (d, J = 5.0Hz, 1H), 7.50-7.39 (m, 3H), 7.29 (t, J = 7.4 Hz, 1H), 7.13-6.97 (m, 2H),6.84-6.61 (m, 2H), 5.21-4.67 (m, 2H), 4.15 (d, J = 12.7 Hz, 1H), 4.03(q, J = 7.1 Hz, 1H), 3.99- 3.90 (m, 1H), 3.74 (d, J = 12.9 Hz, 1H), 3.62(s, 3H), 3.62- 3.48 (m, 1H), 3.46- 3.34 (m, 2H), 3.32 (s, 4H), 3.27 (d,J = 14.2 707.2 NA NA Hz, 1H), 3.22-3.05 (m, 1H), 2.69 (s, 2H), 2.11 (d,J = 2.3 Hz, 3H), 1.99 (s, 2H), 1.26 (dd, J = 6.6, 5.4 Hz, 6H), 1.17 (t,J = 7.1 Hz, 2H). 51

1H NMR (400 MHz, DMSO-d6) δ 9.08- 8.92 (m, 2H), 8.57 (d, J = 5.0 Hz,1H), 8.51 (d, J = 2.3 Hz, 1H), 7.96 (dd, J = 8.1, 2.4 Hz, 1H), 7.94-7.86(m, 1H), 7.42 (d, J = 8.1 Hz, 1H), 6.78- 6.62 (m, 2H), 5.81 (q, J = 5.8Hz, 2H), 4.81 (dd, J = 7.5, 4.2 Hz, 1H), 4.15 (d, J = 12.6 Hz, 2H), 3.95(dd, J = 11.4, 3.7 Hz, 1H), 3.75 (s, 1H), 3.61 (s, 3H), 3.60-3.44 (m,1H), 3.36 (d, J = 12.2 Hz, 1H), 3.26 (dd, J = 14.3, 4.5 Hz, 1H), 3.09(dd, J = 14.3, 745.3 NA NA 11.0 Hz, 1H), 2.04 (s, 3H), 1.17 (s, 9H). 52

1H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 7.5 Hz, 1H), 9.00- 8.89 (m,1H), 8.56 (d, J = 5.0 Hz, 1H), 7.89 (dt, J = 5.0, 1.0 Hz, 1H), 7.17 (d,J = 7.9 Hz, 1H), 7.12 (d, J = 1.7 Hz, 1H), 6.95 (dd, J = 8.0, 1.7 Hz,1H), 6.79 (d, J = 11.7 Hz, 2H), 4.91 (dd, J = 8.7, 3.7 Hz, 1H), 4.66(ddd, J = 9.7, 7.5, 5.1 Hz, 1H), 4.17 (d, J = 12.7 Hz, 1H), 3.96 (dd, J= 11.5, 3.8 Hz, 1H), 3.90-3.72 (m, 2H), 3.70 (s, 3H), 3.67 (s, 3H), 3.61(s, 1H), 3.55 (dd, J = 12.1, 3.6 Hz, 1H), 678.2 NA NA 3.31-3.03 (m, 4H),2.69 (s, 3H). 53

1H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.92 (d, J = 7.8 Hz, 1H), 8.56(d, J = 5.0 Hz, 1H), 7.89 (dt, J = 5.0, 1.0 Hz, 1H), 7.16 (d, J = 7.9Hz, 1H), 7.12 (d, J = 1.7 Hz, 1H), 6.96 (dd, J = 8.0, 1.7 Hz, 1H), 6.79(d, J = 1.17 Hz, 2H), 4.92 (dd, J = 8.8, 3.5 Hz, 1H), 4.60 (ddd, J =9.8, 7.8, 4.4 Hz, 1H), 4.16 (d, J = 12.7 Hz, 1H), 3.96 (dd, J = 11.5,3.8 Hz, 1H), 3.74 (d, J = 13.6 Hz, 2H), 3.70 (s, 3H), 3.61 (d, J = 0.8Hz, 3H), 3.42 (s, 1H), 3.31-3.15 (m, 2H), 664.2 0.2 18.6 3.05 (dd, J =14.1, 9.9 Hz, 1H). 71

1H NMR (400 MHz, DMSO-d6) δ 8.93 (d, J = 7.7 Hz, 1H), 8.51 (d, J = 2.3Hz, 1H), 8.01-7.93 (m, 2H), 7.88 (dd, J = 8.8, 1.0 Hz, 1H), 7.83 (dd, J= 7.4, 1.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 6.71 (d, J = 13.2 Hz, 1H),6.67 (s, 1H), 4.91-4.79 (m, 1H), 4.72 (ddd, J = 10.4, 7.7, 5.1 Hz, 1H),4.14 (m, 3H), 3.95 (dd, J = 11.3, 3.6 Hz, 1H), 3.74 (d, J = 12.2 Hz,1H), 3.56 (s, 3H), 3.52 (m, 1H), 3.36 (d, J = 12.3 Hz, 1H), 3.25 (dd, J= 14.2, 683.2 NA NA 5.3 Hz, 2H), 3.11 (dd, J = 14.2, 10.3 Hz, 1H), 2.10(s, 3H), 1.20 (t, J = 7.1 Hz, 3H). 72

1H NMR (400 MHz, DMSO-d6) δ 12.93- 12.73 (s, 1H), 8.80 (d, J = 8.0 Hz,1H), 8.51 (s, 1H), 7.97 (q, J = 7.6, 6.9 Hz, 2H), 7.88 (d, J = 8.2 Hz,1H), 7.83 (d, J = 7.4 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 6.70 (d, J =13.3 Hz, 1H), 6.66 (s, 1H), 4.84 (s, 1H), 4.72-4.62 (m, 1H), 4.14 (d, J= 12.8 Hz, 2H), 3.95 (d, J = 11.1 Hz, 1H), 3.73 (d, J = 13.3 Hz, 1H),3.56 (s, 3H), 3.55- 3.50 (m, 1H), 3.47- 3.45 (m, 1H), 3.26 655.2 0.184.0 (m, 1H), 3.07 (d, J = 25.1 Hz, 1H), 2.08 (s, 3H). 73

1H NMR (400 MHz, DMSO-d6) δ 8.92 (d, J = 7.8 Hz, 1H), 8.50 (d, J = 2.3Hz, 1H), 8.42 (d, J = 2.0 Hz, 1H), 8.25 (dd, J = 8.8, 2.1 Hz, 1H), 7.95(dd, J = 8.1, 2.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.42 (dd, J = 8.1,0.7 Hz, 1H), 6.71 (dd, J = 12.9, 2.3 Hz, 1H), 6.67 (d, J = 2.4 Hz, 1H),4.84 (m, 1H), 4.73 (ddd, J = 10.4, 7.8, 5.2 Hz, 1H), 4.20-4.05 (m, 3H),3.95 (dd, J = 11.4, 3.6 Hz, 1H), 3.74 (d, J = 12.6 Hz, 683.2 NA NA 1H),3.56 (s, 3H), 3.53 (m, 1H), 3.36 (d, J = 13.4 Hz, 1H), 3.31-3.19 (m,2H), 3.10 (dd, J = 14.2, 10.4 Hz, 1H), 2.07 (s, 3H), 1.20 (t, J = 7.1Hz, 3H). 74

1H NMR (400 MHz, DMSO-d6) δ 13.07- 12.43 (s, 1H), 8.79 (d, J = 8.2 Hz,1H), 8.54-8.46 (m, 1H), 8.41 (d, J = 2.1 Hz, 1H), 8.25 (dd, J = 8.8, 2.1Hz, 1H), 7.94 (dd, J = 8.2, 2.4 Hz, 1H), 7.71 (d, J = 8.9 Hz, 1H), 7.41(d, J = 8.0 Hz, 1H), 6.69 (d, J = 13.0 Hz, 1H), 6.66 (s, 1H), 4.84 (d, J= 9.5 Hz, 1H), 4.70 (ddd, J = 11.9, 8.0, 4.3 Hz, 1H), 4.15 (d, J = 12.6Hz, 1H), 3.98-3.90 (m, 1H), 3.73 (d, J = 12.6 Hz, 655.2 0.14 5.2 1H),3.56 (s, 3H), 3.52 (s, 1H), 3.35 (d, J = 12.4 Hz, 1H), 3.31-3.17 (m,2H), 3.05 (dd, J = 14.2, 11.0 Hz, 1H), 2.05 (s, 3H). 75

1H NMR (400 MHz, DMSO-d6) δ 8.92 (d, J = 7.8 Hz, 1H), 8.49 (d, J = 2.3Hz, 1H), 8.18 (d, J = 8.1 Hz, 1H), 8.11 (d, J = 1.3 Hz, 1H), 7.95 (dd, J= 8.1, 2.4 Hz, 1H), 7.75 (dd, J = 8.0, 1.3 Hz, 1H), 7.41 (dd, J = 8.1,0.2 Hz, 1H), 6.71 (d, J =13.0 Hz, 1H), 6.67 (s, 1H), 4.91- 4.79 (m, 1H),4.73 (ddd, J = 10.4, 7.8, 5.2 Hz, 1H), 4.18- 4.10 (m, 3H), 3.95 (dd, J =11.3, 3.6 Hz, 1H), 3.74 (d, J = 12.7 Hz, 1H), 3.56 (s, 3H), 683.2 NA NA3.52 (m, 1H), 3.36 (d, J = 12.0 Hz, 1H), 3.25 (dt, J = 14.2, 6.9 Hz,2H), 3.09 (dd, J = 14.2, 10.4 Hz, 1H), 2.07 (s, 3H), 1.20 (t, J = 7.1Hz, 3H). 76

1H NMR (400 MHz, DMSO-d6) δ 13.02- 12.67 (s, 1H), 8.79 (d, J = 8.2 Hz,1H), 8.50 (d, J = 2.4 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 8.11 (d, J =1.3 Hz, 1H), 7.94 (dd, J = 8.1, 2.4 Hz, 1H), 7.75 (dd, J = 8.1, 1.3 Hz,1H), 7.45-7.38 (m, 1H), 6.69 (d, J = 13.0 Hz, 1H), 6.66 (s, 1H),4.90-4.77 (m, 1H), 4.69 (ddd, J = 11.9, 8.1, 4.2 Hz, 1H), 4.15 (d, J =12.6 Hz, 1H), 3.95 (dd, J = 11.3, 3.7 Hz, 1H), 3.73 (d, J = 12.5 Hz,655.2 0.16 4.9 1H), 3.56 (s, 3H), 3.52 (m, 1H), 3.36 (d, J = 12.4 Hz,1H), 3.27 (dd, J = 14.1, 4.2 Hz, 2H), 3.05 (dd, J = 14.2, 10.9 Hz, 1H),2.05 (s, 3H). 77

1H NMR (400 MHz, DMSO-d6) δ 8.92 (d, J = 7.8 Hz, 1H), 8.49 (d, J = 2.3Hz, 1H), 8.30 (d, J = 2.3 Hz, 1H), 7.93 (dd, J = 8.1, 2.4 Hz, 1H), 7.45-7.36 (m, 2H), 6.78- 6.68 (m, 1H), 6.67 (d, J = 2.3 Hz, 1H), 4.85 (d, J =8.0 Hz, 1H), 4.73 (m, 1H), 4.14 (m, 3H), 4.04 (s, 3H), 3.95 (dd, J =11.3, 3.6 Hz, 1H), 3.74 (d, J = 12.6 Hz, 1H), 3.55 (m, 4H), 3.36 (d, J =12.3 Hz, 1H), 3.24 (dd, J = 14.1, 4.9 Hz, 2H), 689.3 NA NA 3.09 (dd, J =14.2, 10.4 Hz, 1H), 2.07 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H). 78

1H NMR (400 MHz, DMSO-d6) δ 13.03- 12.58 (s, 1H), 8.79 (d, J = 8.2 Hz,1H), 8.49 (d, J = 2.3 Hz, 1H), 8.30 (d, J = 2.3 Hz, 1H), 7.93 (dd, J =8.2, 2.4 Hz, 1H), 7.42- 7.35 (m, 2H), 6.69 (d, J = 13.5 Hz, 1H), 6.66(s, 1H), 4.85 (m, 1H), 4.75-4.63 (m, 1H), 4.14 (d, J = 12.6 Hz, 1H),4.04 (s, 3H), 3.97-3.90 (m, 1H), 3.73 (d, J = 12.4 Hz, 1H), 3.55 (m,4H), 3.36 (d, J = 12.2 Hz, 1H), 3.27 (dd, J = 14.3, 4.1 Hz, 2H), 661.20.16 3.4 3.11-2.98 (m, 1H), 2.05 (s, 3H). 79

1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.90 (d, J = 7.9 Hz, 1H), 8.61(d, J = 5.0 Hz, 1H), 7.95 (d, J = 5.0 Hz, 1H), 7.31 (d, J = 9.5 Hz, 2H),6.77-6.57 (m, 2H), 4.85 (tt, J = 8.7, 4.6 Hz, 1H), 4.76 (ddd, J = 10.8,7.9, 4.8 Hz, 1H), 4.22-4.09 (m, 3H), 3.95 (dd, J = 11.4, 3.6 Hz, 1H),3.74 (ddd, J = 12.7, 4.0, 2.1 Hz, 1H), 3.66 (s, 3H), 3.63-3.48 (m, 1H),3.41-3.34 (m, 1H), 3.33 (s, 2H), 3.27 (dd, J = 14.2, 4.9 Hz, 1H), 3.08(dd, 694.2 NA NA J = 14.1, 10.8 Hz, 1H), 2.50 (p, J = 1.8 Hz, 2H), 2.10(s, 3H), 1.21 (t, J = 7.1 Hz, 3H). 80

1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.77 (d, J = 8.3 Hz, 1H), 8.61(d, J = 5.0 Hz, 1H), 7.94 (d, J = 5.0 Hz, 1H), 7.29 (d, J = 9.7 Hz, 2H),6.81-6.58 (m, 2H), 4.84 (m, 1H), 4.71 (m, 1H), 4.15 (d, J = 12.6 Hz,1H), 3.95 (dd, J = 11.4, 3.7 Hz, 1H), 3.82-3.69 (m, 1H), 3.65 (s, 3H),3.55 (td, J = 11.3, 3.3 Hz, 1H), 3.44-3.18 (m, 3H), 3.04 (dd, J = 14.2,11.3 Hz, 1H), 2.07 (s, 3H). 666.2 0.06 2.1 81

1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.89 (d, J = 7.8 Hz, 1H), 8.58(d, J = 5.0 Hz, 1H), 7.92 (dd, J = 4.9, 1.1 Hz, 1H), 7.45-7.33 (m, 2H),7.26 (dd, J = 8.1, 1.7 Hz, 1H), 6.79-6.62 (m, 2H), 4.85 (qd, J = 8.8,3.4 Hz, 1H), 4.72 ddd, J = 10.5, 7.7, 5.0 Hz, 1H), 4.14 (m, 3H), 3.95(dd, J = 11.4, 3.6 Hz, 1H), 3.74 (m, 1H), 3.63 (s, 3H), 3.55 (d, J = 3.5Hz, 1H), 3.41-3.17 (m, 6H), 3.07 (m1H), 2.58-2.45 (m, 1H), 698.2 NA NA2.09 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H). 82

1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.94 (d, J = 8.1 Hz, 1H), 8.61(d, J = 5.0 Hz, 1H), 7.94 (d, J = 5.0 Hz, 1H), 7.27 (d, J = 9.5 Hz, 2H),6.79 (d, J = 11.7 Hz, 2H), 4.92 (dd, J = 8.7, 3.6 Hz, 1H), 4.64 (ddd, J= 10.5, 8.0, 4.3 Hz, 1H), 4.16 (d, J = 12.7 Hz, 1H), 3.96 (dd, J = 11.5,3.8 Hz, 1H), 3.74 (ddd, J = 12.7, 4.0, 2.1 Hz, 1H), 3.65 (s, 3H), 3.56(td, J = 11.9, 3.4 Hz, 1H), 3.50-3.39 (m, 1H), 670.2 0.15 4.5 3.27 (dd,J = 14.2, 4.2 Hz, 2H), 3.07 (dd, J = 14.1, 10.6 Hz, 1H). 83

1H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 7.6 Hz, 1H), 9.03 (s, 1H), 8.77(dd, J = 4.4, 1.4 Hz, 1H), 8.61 (d, J = 5.0 Hz, 1H), 8.54 (dd, J = 8.4,1.4 Hz, 1H), 7.95 (d, J = 5.0 Hz, 1H), 7.52 (dd, J = 8.4, 4.4 Hz, 1H),7.29 (d, J = 9.4 Hz, 2H), 6.81 (d, J = 11.6 Hz, 2H), 4.92 (dt, J = 8.9,4.5 Hz, 1H), 4.68 (ddd, J = 10.1, 7.6, 5.2 Hz, 1H), 4.24- 4.08 (m, 3H),3.96 (dd, J = 11.5, 3.8 Hz, 1H), 3.82-3.71 (m, 1H), 3.66 (s, 3H), 676.2NA NA 3.63-3.50 (m, 1H), 3.51-3.31 (m, 5H), 3.25 (m, 2H), 3.12 (m, 1H),1.19 (t, J = 7.1 Hz, 3H). 84

1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.76 (d, J = 8.2 Hz, 1H), 8.58(d, J = 5.0 Hz, 1H), 7.92 (d, J = 4.9 Hz, 1H), 7.43- 7.20 (m, 3H), 6.77-6.59 (m, 2H), 4.84 (dd, J = 8.8, 3.5 Hz, 1H), 4.68 (ddd, J = 11.8, 8.1,4.1 Hz, 1H), 4.15 (d, J = 12.6 Hz, 1H), 3.95 (dd, J = 11.4, 3.7 Hz, 1H),3.63 (s, 3H), 3.60- 3.49 (m, 1H), 3.36 (d, J = 12.3 Hz, 1H), 3.30-3.17(m, 2H), 3.02 (dd, J = 14.2, 11.1 Hz, 1H), 2.06 (s, 648.2 0.05 1.7 3H).85

1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.76 (d, J = 8.1 Hz, 1H), 8.57(d, J = 4.9 Hz, 1H), 8.51 (d, J = 2.4 Hz, 1H), 7.95 (dd, J = 8.1, 2.4Hz, 1H), 7.90 (d, J = 4.9 Hz, 1H), 7.42 (d, J = 8.1 Hz, 1H), 6.54 (d, J= 8.4 Hz, 2H), 6.16 (t, J = 56.3 Hz, 1H), 4.67 (d, J = 12.2 Hz, 1H),4.03 (m, 1H), 3.86 (dd, J = 22.5, 10.7 Hz, 2H), 3.61 (s, 4H), 3.53 (d, J= 11.9 Hz, 1H), 3.43-3.17 (m, 2H), 3.13-2.97 (m, 2H), 2.06 (s, 3H).627.2 3.9 17.9 86

1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.77 (d, J = 8.1 Hz, 1H), 8.57(d, J = 5.0 Hz, 1H), 8.51 (d, J = 2.4 Hz, 1H), 7.95 (dd, J = 8.2, 2.4Hz, 1H), 7.90 (dd, J = 4.9, 0.7 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 6.56(d, J = 12.2 Hz, 2H), 4.69 (ddd, J = 11.8, 8.0, 4.2 Hz, 1H), 4.20 (d, J= 8.7 Hz, 1H), 3.90 (dd, J = 11.5, 3.5 Hz, 1H), 3.78 (d, J = 1.17 Hz,1H), 3.68 (d, J = 11.4 Hz, 1H), 3.61 (s, 3H), 3.59-3.46 (m, 1H),3.43-3.21 (m, 1H), 3.16-2.98 (m, 2H), 645.2 4.2 46.1 2.89-2.74 (m, 1H),2.16 (q, J = 13.4, 12.6 Hz, 1H), 2.06 (s, 3H). 87

1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.77 (d, J = 8.2 Hz, 1H), 8.57(d, J = 4.9 Hz, 1H), 8.50 (d, J = 2.4 Hz, 1H), 7.94 (dd, J = 8.2, 2.4Hz, 1H), 7.90 (dd, J = 5.0, 0.7 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 6.56(d, J = 9.6 Hz, 2H), 4.70 (ddd, J = 12.3, 8.2, 4.2 Hz, 1H), 4.20 (d, J =8.9 Hz, 1H), 3.90 (d, J = 9.1 Hz, 1H), 3.78 (d, J = 11.7 Hz, 1H), 3.68(d, J = 11.6 Hz, 1H), 3.61 (s, 3H), 3.59-3.46 (m, 1H), 3.37-3.17 (m,2H), 3.11-2.96 (m, 2H), 645.2 0.9 19.7 2.86-2.73 (m, 1H), 2.14 (t, J =12.3 Hz, 1H), 2.04 (s, 3H). 88

1H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.92 (d, J = 7.8 Hz, 1H), 8.59(d, J = 5.0 Hz, 1H), 7.92 (dt, J = 5.0, 0.9 Hz, 1H), 7.82 (d, J = 1.9Hz, 1H), 7.80-7.73 (m, 1H), 7.54 (d, J = 8.1 Hz, 1H), 6.75-6.62 (m, 2H),4.85 (tt, J = 8.7, 4.9 Hz, 1H), 4.75 (ddd, J = 10.6, 7.8, 4.9 Hz, 1H),4.21- 4.07 (m, 3H), 3.95 (dd, J = 11.4, 3.7 Hz, 1H), 3.81-3.67 (m, 1H),3.68-3.60 (m, 3H), 3.60-3.47 (m, 1H), 3.42-3.21 (m, 4H), 3.15 (dd, J =14.1, 10.6 Hz, 1H), 2.06 (s, 3H), 1.20 (t, 726.2 NA NA J = 7.1 Hz, 3H).89

1H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.79 (d, J = 8.2 Hz, 1H), 8.59(d, J = 5.0 Hz, 1H), 7.92 (d, J = 4.9 Hz, 1H), 7.82 (d, J = 1.9 Hz, 1H),7.77 (d, J = 8.4 Hz, 1H), 7.66-7.58 (m, 1H), 7.55 (t, J = 7.2 Hz, 2H),6.75-6.56 (m, 2H), 4.85 (dd, J = 8.8, 3.6 Hz, 1H), 4.71 (ddd, J = 11.8,8.1, 4.0 Hz, 1H), 4.14 (d, J = 12.6 Hz, 1H), 3.95 (dd, J = 11.4, 3.7 Hz,1H), 3.73 (d, J = 13.0 Hz, 1H), 3.63 (s, 3H), 3.60- 3.49 (m, 1H), 3.40-3.30 (m, 2H), 3.25 (t, J = 12.2 Hz, 1H), 698.2 0.6 2.3 3.10 (dd, J =14.1, 11.2 Hz, 1H), 2.03 (s, 3H). 90

1H NMR (400 MHz, DMOS-d6) δ 9.02 (s, 1H), 8.79 (d, J = 8.2 Hz, 1H), 8.59(d, J = 5.0 Hz, 1H), 7.92 (dd, J = 5.3, 1.5 Hz, 1H), 7.82 (s, 1H), 7.77(d, J = 8.3 Hz, 1H), 7.55 (t, J = 7.1 Hz, 2H), 6.68 (d, J = 16.9 Hz,2H), 4.91-4.78 (m, 1H), 4.78-4.62 (m, 1H), 4.14 (d, J = 12.6 Hz, 1H),3.95 (dd, J = 11.4, 3.7 Hz, 1H), 3.73 (d, J = 12.6 Hz, 1H), 3.63 (s,3H), 3.59-3.48 (m, 1H), 3.42-3.30 (m, 2H), 3.25 (t, J = 11.9 Hz, 1H),3.16-3.04 (m, 1H), 2.03 (s, 3H). 698.2 0.7 9.7 91

1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.90 (d, J = 7.7 Hz, 1H), 8.59(d, J = 5.0 Hz, 1H), 7.93 (dt, J = 5.0, 0.9 Hz, 1H), 7.47 (td, J = 9.9,8.9, 5.2 Hz, 3H), 6.74- 6.62 (m, 2H), 4.85 (dd, J = 8.8, 3.6 Hz, 1H),4.72 (dd, J = 15.0, 8.3 Hz, 1H), 4.13 (p, J = 7.0 Hz, 3H), 3.95 (dd, J =11.4, 3.7 Hz, 1H), 3.74 (d, J = 12.7 Hz, 1H), 3.64 (s, 3H), 3.61-3.50(m, 1H), 3.36 (d, J = 12.3 Hz, 1H), 3.25 (dd, J = 14.1, 5.3 Hz, 1H),3.11 (dd, J = 14.1, 10.4 Hz, 1H), 2.08 (s, 3H), 1.19 (t, J = 7.1 742.2NA NA Hz, 3H). 92

1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.76 (d, J = 8.2 Hz, 1H), 8.59(d, J = 5.0 Hz, 1H), 7.93 (dt, J = 5.0, 0.9 Hz, 1H), 7.67-7.58 (m, 1H),7.55 (ddd, J = 8.4, 6.5, 4.7 Hz, 1H), 7.52- 7.41 (m, 3H), 6.72- 6.62 (m,2H), 4.85 (dd, J = 8.8, 3.6 Hz, 1H), 4.74-4.62 (m, 1H), 4.14 (d, J =12.6 Hz, 1H), 3.95 (dd, J = 11.3, 3.7 Hz, 1H), 3.79-3.68 (m, 1H), 3.64(s, 3H), 3.60- 3.50 (m, 1H), 3.36 (d, J = 12.3 Hz, 1H), 3.33-3.20 (m,2H), 3.06 (dd, J = 14.3, 11.0 Hz, 1H), 2.04 (d, J = 1.2 Hz, 3H). 714.20.2 1.3 93

1H NMR (400 MHz, DMOS-d6) δ 9.01 (s, 1H), 8.76 (d, J = 8.1 Hz, 1H), 8.59(d, J = 5.0 Hz, 1H), 7.95- 7.89 (m, 1H), 7.51- 7.38 (m, 3H), 6.73- 6.59(m, 2H), 4.84 (d, J = 9.1 Hz, 1H), 4.74- 4.63 (m, 1H), 4.14 (d, J = 12.6Hz, 1H), 3.95 (dd, J = 11.4, 3.6 Hz, 1H), 3.73 (d, J = 12.5 Hz, 1H),3.64 (s, 3H), 3.60- 3.48 (m, 1H), 3.42- 3.16 (m, 3H), 3.06 (dd, J =14.3, 11.1 Hz, 1H), 2.04 (d, J = 1.2 Hz, 3H). 714.2 0.4 25.8

All references, including publications, patents, and patent documentsare incorporated by reference herein, as though individuallyincorporated by reference. The present disclosure provides reference tovarious embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the present disclosure. The descriptionis made with the understanding that it is to be considered anexemplification of the claimed subject matter, and is not intended tolimit the appended claims to the specific embodiments illustrated. Theheadings used throughout this disclosure are provided for convenienceand are not to be construed to limit the claims in any way. Embodimentsillustrated under any heading may be combined with embodimentsillustrated under any other heading.

What is claimed is:
 1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

is a single or double bond; wherein A is an aromatic ring; each Z¹, Z²,Z³, and Z⁴ is independently selected from N, N(CR^(c)), C(O), andCR^(c); wherein each R^(c) is independently selected from H, halo,cyano, hydroxyl, —NR^(a1)R^(a2), C₁₋₄alkyl, C₁₋₄alkoxyl, C₁₋₄haloalkyl,and C₁₋₄haloalkoxyl; R¹ is 5-10 membered heteroaryl or 6-10 memberedheterocyclyl; wherein each 5-10 membered heteroaryl and 6-10 memberedheterocyclyl of R¹ contains one to four N and optionally one to threeC(O) as a ring member(s); and wherein each 5-10 membered heteroaryl and6-10 membered heterocyclyl of R¹ is optionally substituted with one tofour R^(a); and wherein each R^(a) is independently selected from halo,cyano, hydroxyl, —NR^(a1)R^(a2), C₁₋₄alkyl, C₁₋₄alkoxyl, C₁₋₄haloalkyl,C₁₋₄haloalkoxyl, —C₁₋₄alkylene-O—C₁₋₄alkyl, and C₃₋₁₀cycloalkyl; eachR², R³, R⁵, and R⁶ is independently selected from H, halo, cyano,hydroxyl, —NR^(a1)R^(a2), C₁₋₄alkyl, C₁₋₄alkoxyl, C₁₋₄haloalkyl, andC₁₋₄haloalkoxyl; R⁴ is selected from 3-10 membered heterocyclyl, 5-10membered heteroaryl, and —NR^(b1)R^(b2); wherein the 3-10 memberedheterocyclyl and 5-10 membered heteroaryl of R⁴ is optionallysubstituted with one to six R^(b); and wherein each R^(b) isindependently selected from halo, cyano, hydroxyl, —NR^(a1)R^(a2),C₁₋₆alkyl, C₁₋₆alkoxyl, C₁₋₈haloalkyl, and C₁₋₈haloalkoxyl; and whereineach R^(b1) and R^(b2) is independently selected from H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, —C₁₋₆alkylene-phenyl, and—C₁₋₆haloalkylene-phenyl; R⁷ is selected from H, C₁₋₁₀alkyl,C₁₋₁₀haloalkyl, C₃₋₁₀cycloalkyl, 3-14 membered heterocyclyl, C₆₋₁₀aryl,5-10 membered heteroaryl, —C₁₋₄alkylene-NR^(a1)R^(a2),—C₁₋₄alkylene-C(O)NR^(a1)R^(a2), —C₁₋₄alkylene-C₃₋₁₀cycloalkyl,—C₁₋₄alkylene-3-14 membered heterocyclyl, —C₁₋₄alkylene-C₆₋₁₀aryl,—C₁₋₄alkylene-5-10 membered heteroaryl, and -L¹-R⁹; wherein L¹ isselected from —C₁₋₄alkylene-O—, —C₁₋₄alkylene-C(O)—,—C₁₋₄alkylene-O—C(O)—, —C₁₋₄alkylene-O—C(O)—C₁₋₄alkylene-,—C₁₋₄alkylene-C(O)—O—, —C₁₋₄alkylene-C(O)—O—C₁₋₄alkylene-,—C₁₋₄alkylene-O—C(O)—O—, —C₁₋₄alkylene-O—C(O)—O—C₁₋₄alkylene-,—C₁₋₄alkylene-NR^(a1)C(O)—O—, and —C₁₋₄alkylene-O—C(O)—NR^(a1)—; R⁹ isselected from C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-14 memberedheterocyclyl, C₆₋₁₀aryl, and 5-10 membered heteroaryl; wherein eachC₃₋₁₀cycloalkyl, 3-14 membered heterocyclyl, C₆₋₁₀aryl, and 5-10membered heteroaryl of R⁷ and R⁹ is optionally substituted with one tofour groups independently selected from halo, hydroxyl, C₁₋₄alkyl,C₁₋₄alkoxyl, C₁₋₄haloalkyl, C₁₋₄haloalkoxyl, —NR¹¹R^(a2), and—C₁₋₄alkylene-NR^(a1)R^(a2); R⁸ is selected from H, C₁₋₆alkyl, andC₁₋₆haloalkyl; and each R^(a1) and R^(a2) is independently selected fromH, C₁₋₆alkyl, C₁₋₆haloalkyl, and C₃₋₁₀cycloalkyl.
 2. The compound ofclaim 1, wherein the compound is of formula (II):

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim1 or 2, or a pharmaceutically acceptable salt thereof, wherein thecompound is of formula (IIa):

wherein Y¹ is N or CH; R^(d) is selected from H, C₁₋₄alkyl, andC₁₋₄haloalkyl; and r is selected from 0, 1, 2, and
 3. 4. The compound ofany one of claims 1 to 3, or a pharmaceutically acceptable salt thereof,wherein the compound is of formula (IIb):

wherein X¹ is selected from CR^(x1), and N; X² is selected fromCR^(x1)R^(x2), NR^(x2), and O; wherein R^(x1) is selected from H, andR^(b); and R^(x2) is selected from H, C₁₋₄alkyl, and C₁₋₄haloalkyl;R^(d) is selected from H, C₁₋₄alkyl, and C₁₋₄haloalkyl; r is selectedfrom 0, 1, 2, and 3; and m is selected from 0, 1, 2, 3, and
 4. 5. Thecompound of any one of claims 1 to 4, or a pharmaceutically acceptablesalt thereof, wherein the compound is of formula (IIc):

wherein R^(b) is C₁₋₄alkyl, or C₁₋₆haloalkyl; and R^(d) is selected fromH, C₁₋₄alkyl, and C₁₋₄haloalkyl.
 6. The compound of any one of claims 1to 5, or a pharmaceutically acceptable salt thereof, wherein thecompound is of formula (Id):

wherein R^(b) is C₁₋₄alkyl, or C₁₋₆haloalkyl; R^(d) is C₁₋₄alkyl, orC₁₋₄haloalkyl; and each R² and R⁶ is independently selected from halo,C₁₋₄alkyl and C₁₋₄haloalkyl.
 7. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein the compound is offormula (III):


8. The compound of claim 1 or 7, or a pharmaceutically acceptable saltthereof, wherein the compound is of formula (IIIa):

wherein X¹ is selected from CR^(x1), and N; X² is selected fromCR^(x1)R^(x2), NR^(x2), and O; wherein R^(x1) is selected from H, andR^(b); and R^(x2) is selected from H, C₁₋₄alkyl, and C₁₋₄haloalkyl; andm is selected from 0, 1, and
 2. 9. The compound of any one of claims 1,7, and 8, or a pharmaceutically acceptable salt thereof, wherein thecompound is of formula (IIIb):

wherein R^(b) is C₁₋₄alkyl, or C₁₋₆haloalkyl.
 10. The compound of anyoneof claims 1, 2, and 7-9, or a pharmaceutically acceptable salt thereof,wherein R¹ is selected from:

wherein R^(d) is selected from H, C₁₋₄alkyl, and C₁₋₄haloalkyl; andwherein each R¹ is independently optionally substituted with one tothree R^(a).
 11. The compound of any one of claims 1, 2, and 7-10, or apharmaceutically acceptable salt thereof, wherein R¹ is

and wherein R^(d) is C₁₋₄alkyl.
 12. The compound of any one of claims 1,2, and 7-11, or a pharmaceutically acceptable salt thereof, wherein R¹is


13. The compound of any one of claims 1, 2, and 7-9, R¹ is selected from


14. The compound of any one of claims 1, 2, and 7-9, R¹ is


15. The compound of claim 1, wherein Z¹ is N, and each of Z², Z³, and Z⁴is CH.
 16. The compound of claim 1 or 15, or a pharmaceuticallyacceptable salt thereof, wherein each R³ and R⁵ is independentlyselected from H, and halo.
 17. The compound of any one of claims 1, 15,and 16 or a pharmaceutically acceptable salt thereof, wherein each R³and R⁵ is H.
 18. The compound of any one of claims 1-17, or apharmaceutically acceptable salt thereof, wherein each R² and R⁶ isindependently selected from H, halo, C₁₋₄alkyl, C₁₋₄alkoxyl,C₁₋₄haloalkyl, and C₁₋₄haloalkoxyl.
 19. The compound of any one ofclaims 1 to 18, or a pharmaceutically acceptable salt thereof, whereineach R² and R⁶ is independently selected from F, and —CH₃.
 20. Thecompound of any one of claims 1 to 19, or a pharmaceutically acceptablesalt thereof, wherein R² is F, and R⁶ is —CH₃.
 21. The compound of anyone of claims 1-3, 7, and 10-20, or a pharmaceutically acceptable saltthereof, wherein R⁴ is 6-membered heterocyclyl optionally substitutedwith one to three R^(b); and wherein each R^(b) is independentlyselected from halo, C₁₋₄alkyl, and C₁₋₄ haloalkyl.
 22. The compound ofany one of claims 1-21, or a pharmaceutically acceptable salt thereof,wherein R^(b) is selected from —CH₃, —CHF₂, and —CF₃.
 23. The compoundof any one of claims 1-22, or a pharmaceutically acceptable saltthereof, wherein R^(b) is —CF₃.
 24. The compound of any one of claims1-3, 7, and 10-21, or a pharmaceutically acceptable salt thereof,wherein R⁴ is

optionally substituted with R^(b); and wherein R^(b) is selected from—CH₃, —CHF₂, —CF₃, —CH₂CHF₂, and —CH₂CF₃.
 25. The compound of any one ofclaims 1-3, 7, 10-21, and 24, or a pharmaceutically acceptable saltthereof, wherein R⁴ is


26. The compound of any one of claims 1-3, 7, 10-21, and 24-25, or apharmaceutically acceptable salt thereof, wherein R⁴ is selected from


27. The compound of any one of claims 1-3, 7, and 10-20, or apharmaceutically acceptable salt thereof, wherein R⁴ is —NR^(b1)R^(b2);and wherein R^(b1) and R^(b2) is independently selected from H,C₁₋₄alkyl, C₁₋₆haloalkyl, and C₃₋₆cycloalkyl.
 28. The compound of anyone of claims 1-3, 7, 10-20, and 27, or a pharmaceutically acceptablesalt thereof, wherein R⁴ is


29. The compound of any one of claims 4, and 8, or a pharmaceuticallyacceptable salt thereof, wherein X¹ is N, and X² is O.
 30. The compoundof any one of claims 7-12, and 14-29, or a pharmaceutically acceptablesalt thereof, wherein R^(c) is selected from halo, C₁₋₄alkyl,C₁₋₄alkoxyl, C₁₋₄haloalkyl, and C₁₋₄haloalkoxyl.
 31. The compound of anyone of claims 7, 8-12, and 14-30, or a pharmaceutically acceptable saltthereof, wherein R^(c) is selected from F, Cl, CH₃, —OCH₃, —OCF₃, and—CF₃.
 32. The compound of any one of claims 1-31, or a pharmaceuticallyacceptable salt thereof, R⁷ is selected from H, C₁₋₆alkyl, andC₃₋₆cycloalkyl.
 33. The compound of any one of claims 1-31, or apharmaceutically acceptable salt thereof, R⁷ is selected from H, methyl,ethyl, propyl, butyl, cyclopropyl, —CH₂—O—C(O)C(CH)₃, and phenyl. 34.The compound of any one of claims 1-33, or a pharmaceutically acceptablesalt thereof, R⁷ is selected from H, methyl, ethyl, and cyclopropyl. 35.The compound of any one of claims 1-34, or a pharmaceutically acceptablesalt thereof, R⁷ is H.
 36. The compound of any one of claims 1-34, or apharmaceutically acceptable salt thereof, R⁷ is methyl.
 37. The compoundof any one of claims 1-34, or a pharmaceutically acceptable saltthereof, R⁷ is ethyl.
 38. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, R⁸ is H.
 39. A compound, or a pharmaceuticallyacceptable salt thereof, wherein the compound is selected from examples1-93.
 40. A compound, or a pharmaceutically acceptable salt thereof,wherein the compound is selected from:


41. A compound, or a pharmaceutically acceptable salt thereof, whereinthe compound is selected from:


42. A compound, or a pharmaceutically acceptable salt thereof, whereinthe compound is selected from:


43. A pharmaceutical composition comprising a compound of any one ofclaims 1-42, and at least one pharmaceutically acceptable carrier.
 44. Amethod for treating a disease or condition associated with α4β7 integrincomprising administrating to a subject an effective amount of thecompound of any one of claims 1-42, or a pharmaceutically acceptablesalt thereof, or a composition of claim
 43. 45. The method of claim 44,wherein the disease or condition is an inflammatory disease.
 46. Themethod of any one of claims 44-45, wherein the disease or condition isselected from inflammatory bowel disease (IBD), Ulcerative colitis,Crohn's disease, graft-versus-host disease (GVHD), and primarysclerosing cholangitis (PSC).
 47. The method of any one of claims 44-45,further comprising administration of an additional therapeutic compound.48. Use of a compound of any one of claims 1-42, or a pharmaceuticallyacceptable salt thereof, in the manufacture of a medicament for treatinga disease or condition mediated by α4β7 integrin.
 49. Use of a compoundof any one of claims 1-42, or a pharmaceutically acceptable saltthereof, in the manufacture of a medicament for treating an inflammatorydisease.
 50. Use of a compound of any one of claims 1-42, or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for treating inflammatory bowel disease (IBD).